Treatment of ADHD: Drugs, psychological therapies, devices, complementary and alternative methods as well as the trends in clinical trials

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders having a high influence on social interactions. The number of approved treatments and clinical trials for ADHD have increased markedly during the recent decade. This analytical review provides a quantitative overview of the existing pharmacological and non-pharmacological methods of ADHD treatments investigated in clinical trials during 1999-2021. A total of 695 interventional trials were manually assessed from clinicaltrial.gov with the search term « ADHD», and trial data has been used for analysis. A clear majority of the studies investigated non-pharmacological therapies (∼80%), including many behavioral options, such as social skills training, sleep and physical activity interventions, meditation and hypnotherapy. Devices, complementary and other alternative methods of ADHD treatment are also gaining attention. The pharmacological group accounts for ∼20% of all the studies. The most common drug classes include central nervous system stimulants (e.g., methylphenidate hydrochloride, lisdexamfetamine dimesylate, amphetamine sulfate, mixed amphetamine salts, a combination of dexmethylphenidate hydrochloride and serdexmethylphenidate chloride), selective noradrenaline reuptake inhibitors (atomoxetine, viloxazine), and alpha2 adrenergic receptor agonists (guanfacine hydrochloride, clonidine hydrochloride). Several studies investigated antidepressants (e.g., bupropion hydrochloride, vortioxetine), and atypical antipsychotics (e.g., quetiapine, aripiprazole) but these are yet not approved by the FDA for ADHD treatment. We discuss the quantitative trends in clinical trials and provide an overview of the new drug agents and non-pharmacological therapies, drug targets, and novel treatment options.

Keywords: ADHD; agents; drugs; non-pharmacological; pharmacological; stimulants; treatment; trials.

FIGURE 1

The figure presents information about the number of trials among the most widely used pharmacological classes of drugs applied for ADHD treatment in two time intervals (1999–2009 and 2010–2020). The colors of the slices comply with the pharmacological classes. The data is due 4 January 2021.

FIGURE 2

(A) Most common drug targets in ADHD trials. This figure shows targets with the highest number of unique agents drugging the corresponding target in ADHD clinical trials. If a drug had multiple targets, all of these targets were included in the analysis. Protein names have been used to distinguish targets. In total, 12 most common drug targets were included in the figure: sodium-dependent noradrenaline transporter (SLC6A2), sodium-dependent dopamine transporter (SLC6A2), D (2) dopamine receptor (DRD2), sodium-dependent serotonin transporter (SLC6A2), neuronal acetylcholine receptor subunit alpha-4 (CHRNB2), neuronal acetylcholine receptor subunit beta-2 (CHRNA4), 5-hydroxytryptamine receptor 2A (HTR2A), synaptic vesicular amine transporter (SLC18A2), histamine H3 receptor (HRH3), alpha-2A adrenergic receptor (ADRA2A), neuronal acetylcholine receptor subunit alpha-7 (CHRNA7) and alpha-2C adrenergic receptor (ADRA2C). (B) Drug target types in ADHD studies. All data regarding drug target type was collected from go.drugbank.com, genome. jp, and uniprot.org. In order to construct this figure, all unique gene names used in the analysis (82 in total) were taken and then transformed into protein names. Then corresponding proteins have been classified according to four target types: receptor, enzyme, ion channel, transporter. For the gene names S100B (S100 Calcium Binding Protein (B), CARTPT (Cocaine- and amphetamine-regulated transcript protein), and M (Matrix protein 2) no information about the protein type was found, and thus they were placed in group “other”. The data is due 4 January 2021.

FIGURE 3

For the four main classes of interventions such as pharmacological interventions, devices, psychological and complementary and alternative interventions, unique new agents and methods per year were taken. If a study had several interventions, all of them were considered separately. The data is due 4 January 2021.

FIGURE 4

(A) Number of clinical trials per year divided by phases. This figure provides a graphical representation of the number of studies per year for pharmacological, psychological and complementary and alternative methods, categorized by a trial phase for the whole analyzed period (1999–2020). In total, 644 studies were included in the analysis. (B) Number of clinical trials per year divided by stages. For devices, division by stages was used. Stages have been classified as follows: traditional feasibility, first-in-human, and early feasibility stages have been classified as exploratory stage, the pivotal stage has been left as is. This figure shows the number of device studies for the time period from 1999 to 2020. In total, 51 studies were included. The data is due 4 January 2021.

FIGURE 5

(A) Figure 5A illustrates quantitative trends for pharmacological, psychological, complementary and alternative methods and devices. It shows the number of phase 1 studies per year for each method, exept devices, starting from 1999. In oder to show quantitative trends for the device group, studies in exploratory stage were taken. Traditional feasibility, first-in-human, and early feasibility studies have been classified as exploratory stage studies. If there was a combination of interventions in the study, each intervention in this combination was considered separately. (B) Figure 5B depicts in more detail quantitative trends for the psychological group after its division into smaller subclasses: behavior management, cognitive training and psychoeducation. (C) Figure 5C provides information about quantitative trends distribution for complementary and alternative methods class when divided into supplementary and mind-body intervention groups. The data is due 4 January 2021.

FIGURE 6

(A) Number of agents per category and maximal reached phase. The number of discontinued and active agents per category. This graph presents information about unique agents and their maximal reached phase in the following classes: antidepressants, central nervous system stimulants, alpha2 adrenergic receptor agonists, AMPA receptor positive allosteric modulators, alpha7 neuronal nicotinic acetylcholine receptor agonists, antiparkinsonian, atypical antipsychotics, dementia therapeutic agents, histamine H3 receptor antagonists, nootropics, sedative-hypnotics, selective noradrenaline reuptake inhibitors, typical antipsychotics. The colors of the bars show the maximal reached phase or approval status. The right side of the graph depicts the number of active or discontinued agents in the classes presented on the left side. The drug was classified as active if it was not approved and there were clinical trials on it after 2018. The drug was classified as discontinued if it was not approved, and there were no active clinical trials on it after 2018. If there was no completion date for the agent, it was placed in the “without a date” category. The length of the bars is proportional to the number of agents. The colors of the bars show the agent category. (B) Ongoing trials and approved agents The pie charts show the distribution of drug classes in ongoing clinical trials and among approved ADHD agents. The colors of the slices correspond to the pharmacological classes. Trials have been sub-categorized by phase. The data is due 4 January 2021. Abbreviations: ADHD, attention deficit hyperactivity disorder; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, AMPA receptor.