Emerging drugs for the treatment of attention-deficit hyperactivity disorder (ADHD)

Figures & data

Table 1. Experimental treatments in ADHD – drugs with published results

Molecule	Action	Study	Dose range (mg/day)	No of patients (#)	Age (yrs)	Inclusion criteria	Exclusion criteria	Control	Duration (weeks)	Primary outcome	Efficacy opinion*	Safety opinion**
Viloxazine	NRI	Johnson, 2020 [31]	100–400	222	6–12	ADHD-RS-IV ≥ 26	comorbidity	placebo	8	ADHD-RS-IV	1	0
Reboxetine	NRI	Riahi, 2010 [35]	16	40	adult	-	comorbidity	placebo	6	CAARS	1	0
Reboxetine	NRI	Riahi, 2013 [36]	4	25	6–16	comorbid anxiety disorders	comorbidity	none	4	CPRS, HAM-A	+ (non-controlled)	N/A
Edivoxetine	NRI	Jin, 2013 [37]	0.05–0.3 mg/kg	53	6–17	-	comorbidity	none	22 (avg)	ADHD-RS-IV	+ (non-controlled)	N/A
Edivoxetine	NRI	Lin, 2014 [38]	0.1–0.3 mg/kg	340	6–17	-	comorbidity	LA-methylphenidate, placebo	8	ADHD-RS-IV	1	2
Edivoxetine	NRI	Nery, 2017 [39]	0.1–0.3 mg/kg	267	6–17	-	comorbidity	none	5 years	ADHD-RS-IV	- (non-controlled)	N/A
Duloxetine	SNRI	Mahmoudi-Gharaei, 2011 [42]	60	17	11–18	-	comorbidity	none	6	CPRS	+ (non-controlled)	N/A
Duloxetine	SNRI	Bilodeau, 2014 [43]	60	30	adult	CAARS ≥ 20	comorbidity	placebo	6	CAARS	1	0
Bupropion	NDRI	Jafarinia, 2012 [44]	100–150	44	6–17	ADHD-RS-IV 1.5 SD above the norm	comorbidity, substance abuse	methylphenidate	6	ADHD-RS-IV	2	2
Bupropion	NDRI	Hamedi, 2014 [45]	150	42	adult	-	comorbidity, substance abuse	placebo	6	CAARS	1	1
Dasotraline	SNDRI	Koblan, 2015 [46]	4–8	341	adult	ADHD-RS-IV ≥ 26 and previously treated, or 22 and currently treated	comorbidity	placebo	4	ADHD-RS-IV	1	0
Dasotraline	SNDRI	Findling, 2019 [47]	2–4	342	6–12	ADHD-RS-IV ≥ 28	comorbidity, use of psychoactive drugs other than hypnotics	placebo	6	ADHD-RS-IV	1	0
Dasotraline	SNDRI	Wigal, 2020 [48]	4–6	112	6–12	ADHD-RS-IV ≥ 26	comorbidity	placebo	2	SKAMP; PERMP	1	0
Venlafaxine	SNRI	Zarinara, 2010 [51]	50–75	37	6–13	-	comorbidity	methylphenidate	6	ADHD-RS-IV	2 (power issues)	3
Venlafaxine	SNRI	Amiri, 2012 [52]	225	44	adult	Past ADHD diagnosis or relatives of children with ADHD	comorbidity	placebo	6	ADHD-RS-IV	0	0
Tipepidine	GIRK inhibitor	Sasaki, 2014 [55]	30	10	9–11	-	comorbidity	none	4	ADHD-RS-IV	+ (non-controlled)	N/A
Tipepidine	GIRK inhibitor	Tomoda, 2015 [56]	N/A	12	9–11	-	comorbidity	none	4	ADHD-RS-IV	+ (non-controlled)	N/A
Tipepidine	GIRK inhibitor	Dehbozorghi, 2019 [57]	15–30 (add-on)	53	6–12	treatment with methylphenidate	comorbidity	placebo	8	ADHD-RS-IV	1	1
Vortioxetine	SSRI/NaSSA	Biederman, 2019 [58]	10–20	227	adult	AISRS ≥ 24	comorbidity	placebo	12	AISRS	0	0
N-pantoyl-GABA	GABA agonist	Zavadenko, 2017 [33]	30 mg/kg	89	6–12	ADHD-RS-IV ≥ 22 (girls) or 25 (boys)	comorbidity	placebo	16	ADHD-RS-IV	0	1
N-pantoyl-GABA	GABA agonist	Kupriyanova, 2017 [34]	500–1250 (add-on)	24	6–11	inefficacious treatment with atomoxetine	comorbidity	none	8	CHIP	+ (non-controlled)	N/A
Amantadine	NMDA noncompetitive antagonist	Mohammadi, 2010 [59]	100–150	40	6–14	ADHD-RS-IV 1.5 SD above the norm	comorbidity	methylphenidate	6	ADHD-RS-IV	2	3
Memantine	NMDA noncompetitive antagonist	Surman, 2013 [60]	5–20	34	adult	CGI-S ≥ 4	comorbidity	none	12	AISRS	+ (non-controlled)	N/A
Memantine	NMDA noncompetitive antagonist	Mohammadi, 2015 [61]	20	40	6–11	ADHD-RS-IV 1.5 SD above the norm	comorbidity	methylphenidate	6	ADHD-RS-IV	inferior to methylphenidate	0
Memantine	NMDA noncompetitive antagonist	Mohammadzadeh, 2019 [62]	20	40	adult	Past ADHD diagnosis or relatives of children with ADHD	comorbidity	placebo	6	CAARS	1	0
Memantine	NMDA noncompetitive antagonist	Biederman, 2017 [63]	5–20 (add-on)	26	adult	under stimulant treatment, 2 BRIEF-A subscores > 65 T	comorbidity	placebo	12	BRIEF-A	1	1
Fasoracetam	mGluR agonist	Elia, 2018 [64]	50–400	30	12–17	Vanderbilt ≥ 16, mutations in genes of glutamatergic signaling	comorbidity	placebo	5	CGI-S	1	1
Org26576	AMPA positive allosteric modulator	Adler, 2012 [65]	200–600	68	adult	CGI-S ≥ 4, AISRS ≥ 22	comorbidity	placebo	8	AISRS	0	0
Melatonin	MTR agonist	Mohammadi, 2012 [67]	3–6 (add-on)	60	7–12	treatment with methylphenidate	comorbidity	placebo	8	SDSC	0	1
Agomelatine	MTR agonist	Niederhofer, 2012 [68]	25 (add-on)	10	17–19	pharmacological treatment	comorbidity	placebo	4	Wender-Utah rating scale	1	1
Agomelatine	MTR agonist	Salardini, 2016 [69]	15–25	54	6–15	ADHD-RS-IV 1.5 SD above the norm	comorbidity	methylphenidate	6	ADHD-RS-IV	2	2
Molindone	D2/H1 antagonism	Stocks, 2012 [70]	10–40	78	6–12	severe problem behavior	comorbidity	none	12	NCBRF behavior subscale	+ (non-controlled)	N/A
MK-0929	D4 antagonist	Rivkin, 2012 [71]	15	35	adult	AISRS ≥ 20	comorbidity	placebo	9	AISRS	0	1
Sativex	THC+CBD	Cooper, 2017 [72]	10.8 + 10–11.6 + 20	30	adult	CAARS ≥ 24	comorbidity, substance abuse	placebo	6	QbTest	0	1
MK-0249	H3 inverse agonist	Herring, 2012 [73]	10	72	adult	CAARS ≥ 24	comorbidity	LA-methylphenidate, placebo	10	AISRS	0	2
Bavisant	H3 antagonist	Weisler, 2012 [74]	1–10	424	adult	CAARS age-dependent threshold	comorbidity	LA-methylphenidate, atomoxetine, placebo	6	ADHD-RS-IV	0	0
2-pyridylacetic acid	metabolite of betahistine (H3 antagonist, H1 weak antagonist)	Moorthy, 2015 [75]	50–200	16	adult	CAARS ≥ 20	comorbidity	placebo	acute	CPT, SSRT	1	1
Pozanicline	nAChR α4β2 partial agonist	Wilens, 2011 [77]	0.085–0.7 mg/kg	393	6–12	CGI-S ≥ 4	comorbidity, previous non-response to stimulants	atomoxetine, placebo	6	ADHD-RS-IV	0	1
Pozanicline	nAChR α4β2 partial agonist	Apostol, 2012 [78]	2–80	221	adult	CGI-S ≥ 4	comorbidity	placebo	12	CAARS	1	1
Pozanicline	nAChR α4β2 partial agonist	Bain, 2012 [79]	40–80	160	adult	CGI-S ≥ 4	comorbidity	none	8	CAARS	0	0
Sofiniclin	nAChR α4β2 agonist	Bain, 2013 [81]	1–8	243	adult	CGI-S ≥ 4	comorbidity	atomoxetine, placebo	10	CAARS	1	3
AZD1446	nAChR α2β2/α4β2 agonist	Jucaite, 2014 [82]	30–240	79	adult	CGI-S ≥ 4	comorbidity	placebo	12	CAARS	0	1
AZD3480	nAChR α4β2 agonist	Potter, 2014 [83]	5–50	30	adult	CGI-S ≥ 4	comorbidity, smokers	placebo	12	CAARS	1	1

*Efficacy opinion: 0, not different from placebo; 1, superior to placebo; 2, not different from active treatment; 3, superior to active treatment; +, positive opinion (non-controlled study); -, negative opinion (non-controlled study). **Safety opinion: 0, worse than placebo; 1, not different from placebo; 2, not different from active treatment; 3, superior to active treatment.

Table 2. Experimental treatments for ADHD – drugs without public results

Molecule	Group	Action	Status	Age	Sponsor
BLI-1008	noradrenergic	NRI	phase 2 ongoing	adults	BioLite
Centanafadine	serotoninergic/dopaminergic/noradrenergic	SNDRI	phase 3 ongoing	adults	Otsuka
OPC-64005	serotoninergic/dopaminergic/noradrenergic	SNDRI	phase 2 completed	adults	Otsuka
Oxytocin nasal spray	hormone	OTR agonist	phase 1 ongoing	adults	nonprofit
Oxytocin nasal spray	hormone	OTR agonist	phase 2 ongoing	children	nonprofit
CX717	glutamatergic	AMPA positive allosteric modulator	unclear-phase 2
Ampreloxetine	noradrenergic	NRI	discontinued-phase 2
AR08	noradrenergic	unknown, functional agonist	discontinued-phase 2
Bradanicline	cholinergic	nAChR α7 partial agonist	discontinued-phase 2
Brilaroxazine	serotoninergic/dopaminergic	D2, D3, D4, 5-HT1A, 5-HT2A partial agonist and 5-HT2A, 5-HT2B, 5-HT6, 5-HT7 antagonist	discontinued-phase 1
Ciforadenant	purinergic	A2A antagonist	discontinued-phase 2
GlyTI-M	glycinergic	Glycine transporter I inhibitor	discontinued-phase 2
IRL-752	serotoninergic/noradrenergic	5-HT7 antagonist and NE α antagonist	discontinued-phase 1
Opipramol+nicotine	cholinergic/opioid	σ agonist, nAChR agonist	discontinued-phase 2
Vafidemstat	dopaminergic/noradrenergic/other	KDM1A and MAO-B inhibitor	discontinued-phase 2

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