Serotonergic Drugs for the Treatment of Attention-Deficit/Hyperactivity Disorder: A Review of Past Development, Pitfalls and Failures, and a Look to the Future

Abstract

Serotonin has been implicated in the neurobiology of attention-deficit/hyperactivity disorder (ADHD) due to its association with impulsivity, attention, and emotional regulation. Many compounds with serotonergic properties have been evaluated in ADHD, but few have been approved by regulatory authorities. Utilizing a search of public databases, we identified interventions studied in ADHD. Prescribing information and peer-reviewed and gray literature helped us to determine which compounds had an underlying mechanism of action associated with changing serotonin levels. Of the 24 compounds that met the search criteria, 16 had either failed clinical studies in an ADHD population or had been discontinued from future development. The available evidence was assessed to identify the developmental history of drugs with serotonergic activity and the outlook for new ADHD drug candidates targeting serotonin. Several treatment candidates floundered due to an inability to balance effectiveness with safety, underscoring the potential importance of potency, and selectivity. Ongoing drug development includes compounds with multimodal mechanisms of action targeting neurotransmission across serotonin, norepinephrine, and dopamine pathways; it appears likely that treatment which balances competing and complementary monoamine effects may provide improved outcomes for patients. It is hoped that continuing research into ADHD treatment will produce new therapeutic options targeting the serotonergic system, which can positively impact a wide range of symptoms, including mood, anxiety, and sleep as well as attention and hyperactivity.

Introduction

Serotonin (5-hydroxytryptamine [5-HT]) is a key molecule in human physiology, acting as a neurotransmitter within the brain and as a peripheral hormone.¹ Via binding to its receptors in the central nervous system, serotonin modulates a multitude of functions, including various behaviors, mood, sleep, and cognition/memory; an imbalance or deficit within the serotonergic system can result in a range of neurobehavioral disorders, including depression, anxiety, schizophrenia, and addiction.^2,3 Due to its association with attention and behaviors such as impulsivity, aggression, and behavioral inhibition,⁴ serotonin and the 5-HT receptor system are thought to be involved in the neurobiology of attention-deficit/hyperactivity disorder (ADHD).⁵ Moreover, the well-recognized link between deficits in serotonin–receptor binding and negative effects in mood disorders^3,6 is consistent with the symptoms of emotional dysregulation observed in patients with ADHD,^7,8 suggesting significant pathophysiological and symptomatic overlap.

ADHD is a chronic disorder characterized by symptoms of inattention and/or hyperactivity and impulsivity; these symptoms can cause significant distress to patients, as well as impaired function and quality of life.⁹ Data from the Global Burden of Disease study estimated an age-standardized prevalence of 1.13% in 2019, with higher rates in males (1.61%) than in females (0.63%).¹⁰ Although historically considered to be most common in children, with reported prevalence rates of up to 8.0%,^11,12 recent data have suggested a similarly high prevalence among adults (up to 6.76%).^11,13 There has been a large increase in the recognition, diagnosis, and burden of ADHD in the United States over the past 3 decades,¹⁴ with 10.47% of children diagnosed with ADHD in 2022, up from 6.1% in 1997.¹⁵ However, there is controversy as to whether this is due to increased symptom awareness (particularly among females),^16,17 changes to the diagnostic criteria,¹⁶ recognition of higher persistence rates (>90%) into adulthood than previously supposed,¹⁸ or overmedicalization of children.¹⁹ What is clear is that individuals who are diagnosed with ADHD are at elevated risk of social difficulties,^20,21 impaired academic and occupational function,²² psychiatric comorbidities,²³ substance abuse,²⁴ accidental injuries,²⁵ and premature mortality.²⁶

The etiology of ADHD is diverse, encompassing both environmental factors during the period of central nervous system development²⁷ and significant genetic influences (the estimated heritability rate is approximately 80%)²⁸; these result in alterations in brain structure and function, which impact attention, behavior, and impulse control.²⁷ Although the exact neurobiology of ADHD remains uncertain, the neurotransmitters dopamine and norepinephrine are thought to be the key players²⁹; dopamine is known to be involved in impulsive decision-making, motivation/reward, and risk-taking behavior,^30,31 and norepinephrine with attention and arousal.³² This hypothesis was reinforced when drugs targeting the dopamine and norepinephrine pathways proved to be effective in treating ADHD.^29,33 However, approximately one-quarter to one-third of patients do not respond to such therapies,^34–36 and the side effects associated with these treatments may restrict their use.³⁷

Neuroanatomical evidence is consistent with a role for the serotonergic system in ADHD,^38,39 while pharmacological and genetic manipulation of rodent models has implicated the 5-HT system in the hyperactive, impulsive, and mood dimensions of ADHD.⁴⁰ There is an abundance of evidence from both humans and animal models relating to the involvement of serotonin receptors in the occurrence of ADHD,^5,41,42 and a serotonergic hypothesis underpinning ADHD is consistent with the known association between reduced serotonin neurotransmission and mood disorders.⁴³

Based on the assumption that direct serotonergic regulation of relevant brain development and activity influence the neurobiology of ADHD (including both core and associated symptoms), various compounds with serotonergic properties have been studied in populations with ADHD. Thus, a large selection of drugs from classes including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs)—all of which target the 5-HT system—have been evaluated in clinical studies of ADHD, with varying levels of efficacy and/or safety.^44–48 Notably, despite a large number of clinical trials, few such compounds have been approved by regulatory agencies for the treatment of ADHD, possibly because they have inadequate activity on dopamine and/or norepinephrine.

The objective of this evidence-based narrative review is to examine the published literature to identify the developmental history of drugs with serotonergic activity that have been studied in ADHD. We aim to highlight the mechanisms of action, the highest development status—with a focus on the reasons for termination—and the possible underlying causes of why some compounds with serotonergic activity failed in this indication. We will also look at clinical studies reported to be ongoing in the first half of 2024 and assess the potential for future serotonergic treatments in ADHD.

Methods

Information Search and Data Collation

We performed a search using the ClinicalTrials.gov website to identify clinical trials in the field of ADHD. The search was conducted on 23 October 2023, using the search terms ‘ADD’ and ‘ADHD’. The resulting list of 1,610 trials was narrowed further by filtering with the term ‘interventions’. A total of 1,139 intervention trials were retrieved; these were evaluated to identify the individual drug interventions. In addition, a literature search was performed using the PubMed database, Google Scholar, and Google Patents to identify any additional drug interventions not previously captured. All drug interventions identified are listed in Supplementary Table 1.

SUPPLEMENTARY TABLE 1. Initial Interventions Identified for the Treatment of ADHD.

Generic Name(s)		Brand Name(s)
2-pyridylacetic acid		–
Agomelatine		Valdoxan, Thymanax
Amantadine		Gocovri, Osmolex ER, Symmetrel
Amphetamine, dextroamphetamine sulfate, dextroamphetamine-amphetamine		Adderall, Adderall XR, Mydayis, Adzenys XR-ODT, Evekeo, Dezedrine, Zenzedi, Xelstrym
Ampreloxetine, TD-9855		–
AR08		–
Atomoxetine		Strattera
AZD1446		–
AZD3480		–
Bavisant, JNJ-31001074		–
Betahistine HCL		Serc
BLI-1008		–
BP22042013		–
Bradanicline, TC-5619		–
Brexpiprazole		Rexulti
Bupropion		Wellbutrin XL, Wellbutrin SR, Aplenzin, Forfivo XL, Zyban
Cariprazine		Vraylar, Reagila
Centanafadine		–
Clonidine HCl		Clonicel
CX717		–
Dasotraline, SEP-225289		–
Desipramine		Norpramin
Dexmethylphenidate		Focalin
Dimethoxybenzylidene anabaseine, GTS-21, DMXBA		–
Divalproex		Depakote
Duloxetine		Cymbalta
Edivoxetine, LY2216684		n/a
Eszopiclone		Lunesta
Fasoracetam, AEVI-001, LAM 105, MDGN-001, NFC 1, NS 105		–
Galantamine		Razadyne, Reminyl
GlyTI-M		–
Guanfacine HCl, Guanfacine ER, SPD503, TAK-503		Tenex
Imipramine		Tofranil
Lipirinen		Vayarin
Lisdexamfetamine, SPD489, NRP104		Vyvanse
L-methylfolate, 5-MTHF		–
Lobeline		–
L-threonic acid magnesium salt (L-TAMS), MMFS302, MMFS202		–
Mazindol CR		Sanorex, Mazanor
Memantine		Namenda
Metadoxine		Abrixone
Methamphetamine HCl		Desoxyn
Methylphenidate		Ritalin, Aptensio, Concerta, Contempla (NT0102), Daytrana, Jornay PM, Metadate, Quillichew, Quillivant, Rilatine, Medikinet, Adaphen, Addwize, Inspiral, Methmild, Artige, Attenta, Cognil, Equasym, Foquest, Methylin, Penid, Phenida, Prohiper, Tradea, Methylin, Adhansia
MK-0249		–
MK-0929		–
MK-8777, Org 26576, SCH 900777		–
Modafinil		Provigil
Molindone, molindone XR, SPN-810, SPN-810M, AFX-2201, EN-1733A		Moban, Zalvari
Nabiximols		Sativex
Naltrexone		Revia, Depade, Trexan
ND0801		–
Nortriptyline HCl		Pamelor
NS2359, GSK372475		–
Oxytocin nasal spray		–
PDC-1421		–
PF-03654746		–
Pozanicline, ABT-089		–
Reboxetine		Edronax
SEP-228432		–
Serdexmethylphenidate and dexmethylphenidate		Azstarys
Sofinicline, ABT-894		–
Solriamfetol		–
SPD473/BTS 74398		–
TAK-137		–
Tipepidine, tipepidine hibenzate (in Japan)		Asverin, Antupex, Asvelik, Asvex, Bitiodin, Cofdenin A, Hustel, Nodal, Sotal
Tolcapone		Tasmar
Vafidemstat, ORY-2001		–
Varenicline		Chantix
Venlafaxine		Effexor, Vensir, Vencarm, Venlalix, Venlablue
Viloxazine ER, SPN-812		Qelbree
Vortioxetine		Trintellix, Brintellix
Zolpidem		Edluar, Ambien CR, Ambien, Intermezzo, Zolpimist

ADHD, attention-deficit/hyperactivity disorder.

Prescribing information as well as peer-reviewed and gray literature were then searched to determine which of these compounds were reported to have an underlying mechanism of action associated with the neurotransmitter serotonin or its receptor and/or transporter or altered serotonin levels via other mechanisms. We determined that 24 compounds met the criteria of being studied in ADHD and having serotonergic activity, of which 16 were found to have either failed clinical studies in an ADHD population or had been discontinued from future development by the sponsor (Table 1).

Table 1. Interventions for ADHD with a Serotonergic Mechanism of Action that Failed in the ADHD Indication^*.

Drug		Serotonin Mechanism		Serotonin Activity**		Highest Development Status
Amantadine		5-HT3 receptor ligand		5-HT3: IC50 = ~21–32 μM (Human)1 SERT: Ki = 100 μM (Human)2 SERT: Ki = 57–96 μM (Rat)3		• US FDA approved as adjunctive therapy for dyskinesia in PD4
Bavisant		Inverse agonism associated with H3-receptor antagonists increases release of serotonin		–		• Failed ADHD in Phase 25
Brexpiprazole		5-HT1A partial agonist 5-HT2A receptor antagonism		5-HT1A: Ki = 0.12–1.1 nM (Human)6–8 5-HT1A: Ki = 0.09 nM (Rat)7 5-HT1B: Ki = 365 nM (Human)8 5-HT1D: Ki = 23 nM (Human)8 5-HT1E: Ki = >10,000 nM (Human)8 5-HT2A: Ki = 0.47–3.9 nM (Human)6–8 5-HT2A: Ki = 3.8 nM (Rat)7 5-HT2B: Ki = 1.3–1.9 nM (Human)6,8 5-HT2C: Ki = 29 nM (Human)8 5-HT3: Ki = 754 nM (Human)8 5-HT5A: Ki = 614 nM (Human)8 5-HT6: Ki = 117 nM (Human)8 5-HT7: Ki = 3.7–6.6 nM (Human)6,8 SERT: Ki = 247 nM (Human)8		• US FDA approved as adjunctive therapy for MDD in adults, for schizophrenia in patients ⩾ 13 years, and Alzheimer’s disease dementia in adults6 • Reached phase 2 clinical trials for ADHD prior to discontinuation
Dasotraline		Dopamine-norepinephrine-serotonin reuptake inhibitor		SERT: IC50 = 15 nM (Human)9 SERT IC50 = 19 nM (Rat)9		• US FDA rejected NDA for ADHD10 • Development in ADHD discontinued11
Duloxetine		Serotonin and norepinephrine reuptake inhibitor		SERT: IC50 = 3–10 nM (Human)12–17 SERT: Ki = 0.07 nM–9.3 μM (Human)18–24 SERT: Ki = 0.5–8.8 nM (Rat)18,21,25,26 5-HT1A: Ki = >5000 nM (Human)21 5-HT1B: Ki = 3959 ± 810 nM (Human)21 5-HT1D: Ki = >3000 nM (Human)21 5-HT1E: Ki = 3733 ± 618 nM (Human)21 5-HT1F: Ki = 4447 ± 30 nM (Human)21 5-HT2A: Ki = 504 ± 87 nM (Human)21 5-HT2B: Ki = 2100 ± 206 nM (Human)21 5-HT2C: Ki = 916 ± 190 nM (Human)21 5-HT4: Ki = >1000 nM (Guinea Pig)21 5-HT6: Ki = 419 ± 89 nM (Human)21 5-HT7: Ki = 2261 ± 115 nM (Human)21		• US FDA approved for MDD (adults), GAD (adults/pediatric), DPNP (adults), fibromyalgia (adults/pediatric), and CMP (adults)27 • Development in ADHD discontinued
Lobeline		Serotonin reuptake inhibitor		SERT: Ki = >10 μM (Human)28 SERT: Ki = ~46.8 μM (Rat)29,30 5-HT2A: Ki = 7400 ± 1500 nM (Human)31		–
Mazindol CR		Serotonin and norepinephrine reuptake inhibitor		SERT: IC50 = 231 nM (Guinea Pig)2 SERT: Ki = 84–103 nM (Human)33 SERT: Ki = 49.3–272 nM (Rat)34,35 SERT: Kd = ~39 nM (Human)36		• US FDA approved for appetite suppression/obesity management but not currently available37 • Development in ADHD discontinued • Currently being studied for narcolepsy38
Memantine		5-HT3 antagonist		5HT3: IC50 = ~2.2 μM (Human)1 5HT3A: IC50 = 2.29 ± .24 μM (Human)1		• US FDA approved for Alzheimer’s disease dementia39 • Development in ADHD discontinued
MK-0249		SERT activity Inverse agonism associated with H3-receptor antagonists increases release of serotonin		–		• Failed ADHD in Phase 2a40
Modafinil		SERT interactions		SERT: IC50 = >232 μM (Human)41,42 SERT: IC50 = >300 μM (Rat)43 SERT: Ki = 31.3 μM (Rat)44		• US FDA approved to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, OSA, or shift work disorder45 • US FDA did not recommend approval for children with ADHD due to safety concerns46
Molindone		5-HT2B antagonist 5-HT2A antagonist		5-HT2B: IC50 = 0.08–0.41 μM (Human)47 5-HT2A: IC50 = 14 μM (Human)47 5-HT2A: Ki = 320 nM (Human)48 5-HT2A: Ki = 501 nM (Rat)49 5-HT2A: Kd = 5800 nM (Human)50 5-HT1A: Ki = 3797 nM (Human)48 5-HT2C: Ki = >10000 nM (Human)48 5-HT6: Ki = 1008 nM (Human)48 5-HT6: Ki = >5000 nM (Rat)49 5-HT7: Ki = 265–3053 nM (Human)48,51 5-HT7: Ki = 265 ± 36 (Human)49		• Failed ADHD in Phase 352
NS2359		SERT inhibitor Norepinephrine, dopamine, and serotonin reuptake inhibitor		SERT: IC50 = 10 nM (Human)53,54		• Development in ADHD discontinued55 • Most recently studied in cocaine-related disorders55
SEP-228432		Norepinephrine, dopamine, and serotonin reuptake inhibitor		SERT: IC50 = 34 nM (Human)53		–
SPD473/BTS 74398		Non-selective monoamine uptake inhibitor		SERT: Kd = 19 nM56		–
Venlafaxine		Serotonin and norepinephrine reuptake inhibitor		SERT: IC50 = 20–145 nM (Human)20,57 SERT: Ki = 7.8–82 nM (Human)20,21,58 SERT: Ki = 77 nM (Rat)21 SERT: ED50 = 2.0 mg/kg (Rat)21 5-HT1A: Ki = >10000 nM (Human)21 5-HT1B: Ki = >10000 nM (Human)21 5-HT1D: Ki = >10000 nM (Human)21 5-HT1E: Ki = >10000 nM (Human)21 5-HT1F: Ki = >10000 nM (Human)21 5-HT2A: Ki = 2230 nM (Human)21 5-HT2B: Ki = >10000 nM (Human)21 5-HT2C: Ki = 2004 nM (Human)21 5-HT4: Ki = >10000 nM (Guinea Pig)21 5-HT6: Ki = 2792 nM (Human)21 5-HT7: Ki = >10000 nM (Human)21		• US FDA approved for MDD, GAD, SAD, and panic disorder59 • Development in ADHD discontinued • Follow-on compound desvenlafaxine used off-label for ADHD60
Vortioxetine		5-HT3 receptor antagonism 5-HT1A receptor agonism 5-HT7 receptor antagonism 5-HT1B partial agonist 5-HT1D antagonist		5-HT3: Ki = 3.7–23 nM (Human)61,62 5-HT3: IC50 = 12 nM (Human)62 5-HT3: IC50 = 0.18 nM (Rat)62 5-HT3: EC50 = 2100 nM (Human)62 5-HT1A: Ki = 15–39 nM (Human)61–63 5-HT1A: EC50 = 200 nM (Human)62 5-HT1B: Ki = 33 nM (Human)61,62 5-HT1B: EC50 = 120 nM (Human)62 5-HT1D: Ki = 54 nM (Human)61,62 5-HT2C: Ki = 180 nM62 5-HT5A: Ki = 221 nM62 5-HT7: Ki = 19–450 nM (Human)61–63 SERT: Ki = 1.6 nM (Human)61,62 SERT: IC50 = 5.4 nM (Human)61,62 SERT: IC50 = 2.9–5.3 nM (Rat)62,63		• US FDA approved for MDD61 • Failed ADHD at Phase 264

*References for this table can be found in the Supplementary Materials.

**Species has been identified as reported.

5-HT, 5-hydroxytryptamine; ADHD, attention-deficit/hyperactivity disorder; CMP, chronic musculoskeletal pain; DPNP, diabetic peripheral neuropathic pain; EC₅₀, half maximal effective concentration; ED₅₀, the dose of a medication that produces a specific effect in 50% of the population that has been administered that dose; GAD, generalized anxiety disorder; IC₅₀, half-maximal inhibitory concentration; Kd, dissociation constant; Ki, inhibition constant; MDD, major depressive disorder; NDA, New Drug Application; OSA, obstructive sleep apnea; PD, Parkinson’s disease; PFC, prefrontal cortex; SAD, social anxiety disorder; SERT, serotonin transporter; US FDA, United States Food and Drug Administration.

Failed/Discontinued Compounds

Broadly, the 16 compounds that were found to have failed/been discontinued for ADHD were divided into three categories. These were (i) 5-HT receptor activity: amantadine, brexpiprazole, memantine, molindone, and vortioxetine (also has considerable serotonin transporter [SERT] inhibition); (ii) SERT activity: dasotraline, duloxetine, lobeline, mazindol CR, modafinil, NS2359, SEP-228432, SPD473/BTS 74398, and venlafaxine; and (iii) histamine H₃ receptor inverse agonism, which increases serotonin release⁴⁹: bavisant and MK-0249.

For those agents approved in other indications (vortioxetine, brexpiprazole, venlafaxine, duloxetine, and mazindol CR), the mechanism of action was obtained from the prescribing information. Where no prescribing information was available, the potential mechanism of action was deduced from the published scientific literature or other public domain sources.

5-HT Receptor Agonist/Antagonists

Amantadine

Although the exact mechanism of action of amantadine is unknown, it is thought to be a weak antagonist of the N-methyl-D-aspartate (NMDA) receptor.⁵⁰ In addition, it has been shown in vitro to bind to 5-HT₃ receptors.⁵¹

Several studies evaluating amantadine in ADHD have been published. In an open-label, uncontrolled trial of amantadine given orally to 24 patients aged 5–13 years, symptoms were evaluated at baseline and week 6 using parent and teacher ADHD rating scales (ADHD-IV rating scale).⁵² Treatment was titrated from 50 mg/day for 4 days to 100 mg/day for an additional 4 days, and finally to 150 mg/day. At week 6, the parent ADHD score had decreased from 41.04 ± 6.9 at baseline to 28.9 ± 8.7 (p < 0.001, effect size d = 1.5), and the teacher ADHD score from 35.8 ± 9.6 to 26.2 ± 9.5 (p < 0.001, effect size d = 1.0). Half of the patients (13/24) reported adverse events (AEs), of whom one discontinued treatment. The most common AEs were transient decrease in appetite (n = 5) and headache (n = 4).⁵²

A randomized clinical trial in children treated with amantadine (100–150 mg/day depending on weight) or the stimulant methylphenidate (MPH) for 6 weeks showed similar improvements in ADHD symptoms with both drugs, with no significant differences between treatments on parent ADHD rating scale scores. The two types of AEs that differed significantly between treatment groups were decreased appetite (45% amantadine and 85% MPH) and restlessness (5% amantadine and 40% MPH).⁵³ In a retrospective study of 297 pediatric patients with psychiatric symptoms, including 251 with ADHD, amantadine (⩽400 mg/day) appeared to be an effective treatment, with a success rate of 64.5% in improving symptoms.⁵⁴ In addition, given that 48.1% of amantadine responders were receiving combination therapy with a stimulant (e.g., MPH or amphetamine), these data suggested that amantadine could also serve as a viable adjunct to stimulant treatment. Amantadine was also well-tolerated, with just 17/297 patients (5.7%) discontinuing due to AEs.⁵⁴

Although these studies suggested that amantadine was safe and efficacious for the treatment of ADHD, no consistent dosage or regimen has been determined, and no further clinical development has been identified since 2021. This may be because the drug is available in generic forms, and no manufacturer is willing to sponsor the official clinical trial program that would be necessary to obtain regulatory approval.

Brexpiprazole

Brexpiprazole has high receptor binding affinity to norepinephrine, serotonin, and dopamine receptors. It is an antagonist at norepinephrine α1B and α2C receptors and serotonin 5-HT_2A receptors, as well as partial agonist activity at serotonin 5-HT_1A and dopamine D₂ receptors.^55,56

Data relating to the use of brexpiprazole in ADHD comes primarily from a randomized placebo-controlled phase 2 trial in 559 stimulant-naïve adults and 174 prior stimulant-nonresponding adults with ADHD, in which all participants received stimulants for 5 weeks.⁵⁷ After this period, 168 stimulant-naïve patients and 68 prior stimulant nonresponders who failed treatment were randomized to receive either adjunctive brexpiprazole or placebo. When assessed using scales including the Conners’ Adult ADHD Rating Scale (CAARS), Montgomery-Asberg Depression Rating Scale, Beck Depression Inventory, Clinical Global Impression (CGI), and the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), stimulant-naïve patients were found to have no improvement with adjunctive brexpiprazole, while prior stimulant nonresponders showed a tendency toward treatment benefit only on the WRAADDS scale. AEs were similar in the brexpiprazole and placebo groups.⁵⁷

Brexpiprazole is indicated for the treatment of other psychiatric disorders; however, development for the treatment of ADHD was terminated by the sponsor following phase 2 clinical study.

Memantine

Like amantadine, memantine is an NMDA receptor antagonist,⁵⁸ which in vitro has been shown to have antagonistic actions at 5-HT₃ receptors.⁵¹ In a randomized placebo-controlled clinical trial study of 40 adult patients (18-45 years) with ADHD, 6 weeks of treatment resulted in significant differences in behavior and attention deficit between patients treated with memantine and those receiving placebo (p < 0.001). Treatment with memantine was reported to be tolerable, with mild AEs.⁵⁹

Memantine has been approved by the US Food and Drug Administration (FDA) as a treatment for Alzheimer’s disease since 2003,⁵⁸ with no further clinical development in ADHD.

Molindone

Molindone is an antipsychotic medication used historically for the treatment of schizophrenia,⁶⁰ although the original clinical development sponsor (Endo Pharmaceuticals, Inc.) discontinued production in 2010 due to manufacturing/sourcing difficulties.⁶¹ In vitro studies have shown that at therapeutic concentrations molindone is a potent antagonist for dopamine receptors D_2S and D_2L and the serotonin receptor 5-HT_2B.⁶²

Data from phase 2 studies in children with ADHD suggested that adjunctive (to MPH or amphetamine) molindone treatment was able to produce improvements in behavior, particularly symptoms of persistent impulsive aggression.^63,64 A new formulation of molindone was utilized by Supernus Pharmaceuticals in the phase 3 studies CHIME 1 (NCT02618408) and 2 (NCT02618434), as well as the open-label extension study CHIME 4 (NCT02691182), for the treatment of impulsive aggression in children in conjunction with standard ADHD treatment. Although the results have not been published in a peer-reviewed journal, data published on the trial registration website indicate that the studies failed to meet the primary endpoints. Despite dropping the lower dose arm (18 mg/day) of the CHIME 1 and 2 studies after interim analyses,⁶⁵ no statistical differences were observed between molindone 36 mg/day and placebo in the frequency of impulsive aggression (NCT02618408, NCT02618434, NCT02691182). AEs occurred in up to 19% of patients in the higher dose arm. A further study (NCT03597503) was planned in adolescents but was terminated due to business decisions, which were unrelated to safety. Subsequently, all clinical development activities for molindone in ADHD were halted.⁶⁶

Vortioxetine

Vortioxetine is a serotonin modulator approved for major depressive disorder, which exerts its effects via 5-HT₃, 5-HT_1A, and 5-HT₇ receptor antagonism, as well as 5-HT_1B partial agonism and 5-HT_1D antagonism.^67,68 Vortioxetine has also shown moderate to high affinity for SERT.⁶⁷

A proof-of-concept study was reported in 2019, in which 227 adult patients (18-55 years) with a diagnosis of ADHD received treatment with vortioxetine (10 or 20 mg/day) or placebo for 6 weeks. ADHD symptoms were assessed using the Adult ADHD Investigator Symptom Rating Scale (AISRS); although symptoms improved with both vortioxetine doses, there were no statistically significant differences from placebo. Both doses were well-tolerated.⁶⁹ As the drug failed to meet the primary endpoint in this proof-of-concept study, no further development in ADHD was undertaken.

SERT Activity

Dasotraline

Dasotraline is a potent inhibitor of the dopamine and the norepinephrine transporter, and a weak inhibitor of SERT.⁷⁰ Dasotraline was evaluated for the treatment of ADHD in an extensive clinical development program, including several late-phase placebo-controlled studies, yet failed to produce data sufficient to obtain regulatory approval.

In a placebo-controlled phase 2/3 study, treatment with dasotraline 4 mg/day was reported to significantly improve the symptoms and behaviors associated with ADHD (specifically attention and hyperactivity) in children aged 6–12 years.⁷¹ However, 2 mg/day of dasotraline did not differ significantly from placebo on the primary endpoint of ADHD Rating Scale Version IV–Home Version (RS-IV HV) score or secondary efficacy measures. Common dasotraline-related AEs included insomnia, decreased appetite, decreased weight, and irritability, and 12.2% of patients receiving dasotraline 4 mg/day discontinued treatment, compared with 1.7% in the placebo group.⁷¹ Dasotraline 4 mg/day was also found to be efficacious and generally well-tolerated in a phase 3 placebo-controlled, laboratory classroom study of children (aged 6–12) with ADHD.⁷² Compared with placebo, dasotraline significantly improved scores on the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP)–combined score (dasotraline −3.2, placebo +2.0; p < 0.001; effect size = 0.85). Children showed improvements in the attention and deportment subscale scores. In line with the prior phase 2/3 study, the most frequent AEs associated with dasotraline were insomnia (19.6%), headache (10.7%), and decreased appetite (10.7%); 5.4% of dasotraline-treated patients discontinued the study compared with 1.8% in the placebo group.⁷²

Dasotraline was also evaluated in a phase 3, placebo-controlled study of adults (18-55 years) with ADHD, at doses of 4 or 6 mg/day.⁷³ However, neither dose was found to be significantly better than placebo in terms of the primary endpoint (reduction in ADHD RS-IV HV total score), although the 6-mg/day dose produced a significant effect at week 8 using unadjusted data. The most frequent AEs occurring with dasotraline (vs placebo) were insomnia, decreased appetite, dry mouth, and anxiety; these appeared to be dose-related.⁷³

Based on these clinical trial data, the US FDA rejected a new drug application (NDA) for dasotraline in ADHD, citing the need for additional studies to more fully determine its efficacy and tolerability for this indication.⁷⁴ The sponsor subsequently announced the withdrawal of the NDA and stated their intention to discontinue the clinical development program.⁷⁵

Duloxetine

Duloxetine is a member of the SNRI drug class, being a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less-potent inhibitor of dopamine reuptake.⁷⁶

Duloxetine is indicated for the treatment of several psychiatric disorders,⁷⁶ and was evaluated in a 6-week double-blind, placebo-controlled trial in 30 adults (18–50 years) with ADHD.⁷⁷ Efficacy results were mixed; duloxetine 60 mg/day had greater improvements on CGI-Severity scores (3.00 vs 4.07 for placebo; p < 0.001) and CGI-Improvement scores (2.89 vs 4.00; p < 0.001), plus greater decreases on 5 of 8 subscales of the CAARS at week 6. However, there was no effect on depression or anxiety. At week 1, 80% (12/15) of participants receiving duloxetine reported AEs, and 6 participants stopped treatment as a result.⁷⁷ No additional studies of duloxetine in ADHD were identified, with no further clinical development for duloxetine in this indication.

Lobeline

Lobeline is a potent antagonist at both the α3β2 and α4β2 neuronal nicotinic receptor subtypes, and appears to perturb dopamine storage and release mechanisms.⁷⁸ In vitro pharmacological evaluation has also suggested potency and selectivity for SERT inhibition.⁷⁹

The effects of sublingual lobeline (7.5, 15, or 30 mg) was assessed in a proof-of-concept study using cognitive tasks and self-report measures in 9 adult volunteers (21–45 years) with ADHD. The results indicated a modest improvement in working memory but no significant improvement in attention. Patients reported not liking the taste, and nausea appeared to be a dose-related AE.⁸⁰ A follow-on phase 2 clinical trial of sublingual lobeline was conducted in 13 adult patients with ADHD (NCT00664703); although the study was completed, no results have been reported to date. It is assumed that the data were not positive and that no further development was warranted.

Mazindol CR

Mazindol is an anorexiant that produces stimulatory effects on the central nervous system similar to those produced by amphetamines.⁸¹ Mazindol has been shown to alter neuronal catecholamines via its activity as an SNRI⁸¹ and was recently reported to be a partial orexin-2 receptor agonist and triple monoamine reuptake inhibitor.⁸²

Mazindol controlled release (1–3 mg/day) was evaluated in a randomized, double-blind, placebo-controlled 6-week trial in 85 adults (aged 18–65) with ADHD.⁸³ Based on ADHD-rating scale (ADHD-RS-DSM5) scores, mazindol improved symptoms to a greater extent than placebo (least squares mean −18.9 vs −5.7; mean difference −13.2 [95% confidence interval {CI} −18.7 to −7.6]; effect size 1.09), with differences observable from day 7. Treatment was reported to be well-tolerated, with no serious AEs, and no discontinuations due to treatment-emergent adverse events. A small effect on heart rate, similar to that produced by class II stimulants, was noted.⁸³

Although the study authors noted that phase 3 studies were planned for mazindol in ADHD,⁸³ according to ClinicalTrials.gov no such studies have been identified. Mazindol is currently being studied for narcolepsy (NCT05055024, NCT04923594, NCT05914194),⁸⁴ and it could be assumed that the lack of clinical developmental progress in ADHD was a business decision.

Modafinil

Modafinil is a compound with wakefulness-promoting properties similar to those of amphetamines and MPH; its exact mechanism of action is unknown but appears to involve dopamine reuptake, as well as release of histamine and orexin.^85,86 Data from animal studies have also indicated a dose-dependent interaction with SERT, thereby increasing dialysate serotonin levels.⁸⁷

A meta-analysis of five clinical trials in a pediatric population with ADHD concluded that modafinil produced greater improvements in ADHD-RS-5 home (standardized mean difference, −0.77 [95% CI −1.11 to −0.44]) and school (−0.71 [95% CI −0.96 to −0.47]) scores compared with placebo. The most common AEs with modafinil were decreased appetite and insomnia. Discontinuation rates due to AEs were similar to the control group.⁸⁸ Despite positive trial data, the US FDA advisory committee did not recommend approval of modafinil for children with ADHD because of panel members’ concern of modafinil’s potential to cause Stevens-Johnson syndrome.⁸⁹

Although development of modafinil in this indication was terminated, it has been used off-label to treat ADHD.⁹⁰ In addition, the follow-on drug armodafinil (an R-enantiomer of modafinil) is reported to be in use as a ‘smart drug’ to improve cognition in healthy individuals and has been used to treat ADHD off-label.⁹¹ However, studies with armodafinil have shown no significant effect on serotonin or its receptor.⁹²

NS2359

NS2359 is a mixed monoamine reuptake inhibitor with equipotent effects on norepinephrine and dopamine transporters as well as SERT.⁹³

In a phase 2a study in 126 adults with ADHD, no significant differences between NS2359 and placebo in terms of the primary outcome measure (reduction in investigator-rated ADHD-RS total score) were observed (7.8 vs 6.4; p < 0.45). Overall, NS2359 had no effect on ADHD symptoms, although subgroup analyses suggested a modest improvement in attention and authors noted a low dose as a potential cause. The most frequent treatment-related AE was insomnia; no serious AEs were reported.⁹³ Further clinical development of NS2359 in ADHD was discontinued.⁹⁴

SEP-228432

SEP-228432 (also called SEP-432) is a triple reuptake inhibitor of serotonin, norepinephrine, and dopamine.⁹⁵ The manufacturer (Sepracor Inc.) reported an interest in developing this compound for ADHD,⁹⁶ which was further reported in 2010 with the acquisition of Sepracor Inc. by Sumitomo Pharma.⁹⁷

A phase 1 study in healthy volunteers (NCT01531972) was completed to ascertain the pharmacokinetics, as well as SERT and dopamine transporter (DAT) occupancy, by single-photon emission computed tomography (SPECT).⁹⁸ However, by 2012, no further clinical development for SEP-228432 in ADHD had been reported.⁹⁹

SPD-473

SPD-473 (also called BTS 74 398) is a mixed monoamine (serotonin, dopamine, and norepinephrine) reuptake inhibitor.¹⁰⁰ It was reported to have completed phase 1 development in ADHD,^100,101 but it appears that clinical development activities in all indications have subsequently ceased.^100,101

Venlafaxine

Venlafaxine is an SNRI indicated for the treatment of several psychiatric disorders¹⁰² and has been evaluated for the treatment of ADHD in several controlled and uncontrolled clinical trials.^46,103

In an open-label study of 9 adult patients (18–65 years), treatment with venlafaxine was associated with significant reductions in ADHD symptomatology at Week 2 (ADHD-RS, p < 0.02; CGI, p < 0.006), with 7/9 patients being considered responders, and only mild-to-moderate AEs being reported.¹⁰⁴ A subsequent 6-week double-blind trial in 44 adults with ADHD failed to find a significant difference between venlafaxine and placebo in the effect on ADHD symptoms. No serious AEs were reported.¹⁰⁵ A meta-analysis of 10 studies concluded that venlafaxine showed some efficacy in the treatment of ADHD, but was less potent than duloxetine.⁴⁶ Despite the lack of official regulatory approval for this indication, venlafaxine has been reported to be used for the treatment of ADHD.¹⁰⁶

Histamine H₃ Receptor Inverse Agonism

Bavisant

An H₃ receptor antagonist, bavisant was considered a good candidate for potential use in the treatment of attention and cognitive disorders¹⁰⁷ and has been evaluated in several studies in ADHD.

In a randomized, double-blind, placebo- and active-controlled phase 2 study evaluating three dosages of bavisant (1, 3, or 10 mg/day) in adults with ADHD, the mean change in the total ADHD-RS-5 score with bavisant was −9.3 (1 mg), −11.2 (3 mg), and −12.2 (10 mg) versus −8.8 in the placebo group. For the 10-mg/day group, the change was not statistically superior to placebo (p = 0.161) and no further hierarchical testing was conducted. The highest dosage of bavisant was poorly tolerated (89.0% experienced AEs and 19.2% discontinued as a result).¹⁰⁷ Three early-stage studies in children (NCT00890240 and NCT00890292) and adults (NCT00566449) with ADHD were also completed, but to date, no results have been published.

MK-0249

MK-0249 was a developmental compound investigated in various cognitive defects, including ADHD,¹⁰⁸ sleepiness associated with obstructive sleep apnea,¹⁰⁹ and Alzheimer’s disease.¹¹⁰ MK-0249 administration acts on the H₃ receptor to increase histamine release,¹⁰⁸ which is pro-cognitive and could assist with ADHD symptoms; the H₃ receptor also acts as a heteroreceptor that regulates the release of neurotransmitters such as serotonin.¹⁰⁸

In a randomized, double-blind, placebo-controlled, crossover phase 2a study of MK-0249 (5-10 mg/day) versus MPH, MK-0249 did not differ from placebo (p = 0.341) in terms of AISRS scores, whereas MPH produced significant improvements (p < 0.001). Although MK-0249 was reported to be generally well-tolerated, 5/37 (13.5%) patients discontinued treatment due to AEs, compared with 6.8% in the MPH group and 3.7% in the placebo groups. A greater percentage of patients reported insomnia with MK-0249 treatment compared with placebo (32% vs 11%, respectively).¹⁰⁸ Given the unfavorable outcome in this study, plus failures in the studies for obstructive sleep apnea¹⁰⁹ and Alzheimer’s disease,¹¹⁰ further clinical development of MK-0249 was discontinued.

Discussion

Evaluating the Developmental Failures

Due to the large body of evidence indicating a role for 5-HT in mood disorders,^2,3 and their very high comorbidity in patients with ADHD, many pharmaceutical companies have looked at serotonergic compounds for the treatment of ADHD, with mixed success. For every drug that has been approved in this field, several others have either failed clinical trials or have been withdrawn from development. Some compounds were assessed in a clinical trial program involving multiple randomized studies yet still failed to generate data that were sufficiently robust to obtain regulatory approval. Other compounds, despite showing promise in early-stage trials, were not investigated further, possibly because there was no sponsor willing to fund the trials likely needed to progress to an NDA or for other business-related reasons. The reasons for discontinuation or non-approval are multifactorial, with study design factors such as patient selection, ADHD diagnostic criteria, and scales and endpoints each playing a part. However, it is also possible that patient selection and appropriate dose selection, including the need to balance effectiveness with safety may underlie at least some of the problems observed during drug development for ADHD.

Potency and selectivity are key attributes when considering efficacy and tolerability. Off-target effects resulting in AEs may reduce the dosage range for a particular compound, thereby decreasing the ability of the prescribing physician to maximize its effectiveness sufficiently to control symptoms. As shown in Table 1, the reported half-maximal inhibitory concentrations (IC₅₀) and inhibition constants (Ki) vary widely among the drugs described here, suggesting that each will have a different benefit-risk profile during ADHD treatment.

Moreover, specific serotonergic efficacy and tolerability effects are likely to be further complicated by AEs elicited in response to the other effects of a given drug, e.g., toxicity driven by binding to/inhibition of noradrenaline and dopamine receptors and transporters. However, this level of information would require a much deeper investigation of the exact mechanism of action than is available for many approved and failed ADHD treatment candidates, several of which remain imperfectly understood. It is likely that there is a ‘Goldilocks zone’, in which the effects in the brain are sufficient to manage ADHD symptoms without triggering the type and severity of AEs likely to lead to discontinuation. In support of this, we note that several studies of failed drugs (including amantadine, molindone, dasotraline, and bavisant) struggled to determine an optimal dose, and some approved drugs (notably amphetamines and MPH) are routinely titrated by physicians in an attempt to obtain the best outcomes. Patterns of drug administration (for short durations or intermittently) may also limit the therapeutic value of developmental serotonergic drugs.¹¹¹ The fact of a particular compound having a known serotonin effect and proven efficacy in other neurobehavioral disorders may not be enough to indicate that it should be tested for effectiveness in ADHD. Instead, a deeper understanding of its potency and selectivity appears necessary before embarking on clinical trials.

Current Treatment Landscape of Serotonergic Drugs Used in ADHD

Several of the best-known and most commonly used pharmacological treatments for ADHD are associated with effects on serotonergic neurotransmission. Amphetamines are non-catecholamine, sympathomimetic amines,^112–114 but have also been shown to have affinity for SERT, thereby increasing extracellular serotonin.^115,116 Amphetamines have been shown to robustly improve the severity of ADHD symptoms but are associated with AEs (e.g., elevated blood pressure, cardiovascular conditions, gastrointestinal symptoms, decreased appetite, long-term suppression of growth, and neuropsychiatric symptoms, such as irritability, mania, and psychosis^117,118) that can result in high discontinuation rates.¹¹⁹

The mechanism of action of MPH in ADHD is not fully understood, but it is thought to block dopamine and norepinephrine reuptake.^120,121 The evidence for a serotonergic role is not as conclusive as for amphetamines; the affinity of MPH for SERT is lower than for dopamine or norepinephrine transporters,¹²² although MPH has been reported to have agonist activity at the 5-HT_1A receptor.¹²³ Some researchers have found no indication of an MPH effect on 5-HT pathways,¹¹⁵ while others have suggested that MPH administration can rebalance serotonin levels in the brain and blood, thereby reducing hyperactivity^124,125 and synchronizing biological rhythms¹²⁶ in patients with ADHD. The relative activity on the serotonin system for a given patient could be subject to inter-individual variability. MPH is widely used in ADHD, although studies have shown that dosing and clinical response are variable,¹²⁷ likely due to genetic differences in the activity of the carboxylesterase 1 enzyme, which metabolizes MPH,¹²⁸ and as a result of titration in an attempt to minimize AEs.¹²⁹

Atomoxetine is reported to be a selective NRI¹³⁰ but has also been shown to bind in vitro to SERT.¹³¹ The effectiveness of atomoxetine was established following an extensive development program involving multiple randomized controlled clinical studies in both children (4 studies) and adults (2 studies).^132,133 Viloxazine ER, another selective NRI,¹³⁴ has also been shown to increase brain serotonin levels via its actions at 5-HT receptors (5-HT_2B and 5-HT₇ antagonist and 5-HT_2C agonist).¹³⁵ It can be hypothesized that the 5-HT_2C agonist activity of viloxazine regulates dopamine signaling in both the midbrain and striatal regions via interactions with gamma-aminobutyric acid interneurons,^136–139 which have been shown to reduce impulsive behavior.¹⁴⁰

In addition, there are several drugs which have some degree of serotonergic activity that are not approved by the US FDA for the treatment of ADHD but are nonetheless reported to be used for this purpose (often concomitantly alongside stimulants). Agomelatine is a melatonin agonist and selective serotonin antagonist, with effects at 5-HT_2C and 5-HT_2B receptors.^141–143 It is currently approved in other countries, but not in the US, for the treatment of adult depression,¹⁴¹ and has been reported to have psychostimulant activities, with the ability to regulate cognitive activity and circadian rhythms.¹⁴³ In a small clinical trial in ADHD, the addition of agomelatine to MPH or atomoxetine suggested clinical efficacy, particularly in terms of the impact on comorbid sleep, anxiety, or oppositional defiance disorder.¹⁴⁴ In another study, agomelatine monotherapy was found to be as effective as MPH on parent and teacher rating scale scores.¹⁴⁵ Across all published studies and indications, agomelatine is considered well-tolerated with high levels of adherence.¹⁴³

The TCA desipramine is indicated for the treatment of depression in the US¹⁴⁶ and has been reported to be used in the treatment of ADHD.^147,148 It appears to exert its effects via blocking norepinephrine and serotonin reuptake,¹⁴⁸ and has been reported to alter 5-HT receptor sensitivity.¹⁴⁹ However, although clinical studies in ADHD have indicated that desipramine can decrease clinical symptoms, there are serious concerns regarding its safety, particularly in children.¹⁵⁰ Imipramine is another TCA indicated in the US for depression¹⁵¹ and has been linked to the treatment of ADHD,¹⁵² although the clinical data supporting its use are older.⁴⁵ It exerts a serotonergic effect via inhibition of SERT and alterations in 5-HT_1A receptor sensitivity.^153,154

Compounds Currently in Development

Several compounds with some degree of serotonergic activity are currently in clinical development for the treatment of ADHD. It will be of future interest to assess the final regulatory outcome in the light of what is known about the serotonergic potency and selectivity of each of these drugs.

Cariprazine is an atypical antipsychotic indicated by the US FDA for several psychiatric disorders.¹⁵⁵ It acts as a partial agonist at the dopamine D₂ and D₃ receptors and serotonin 5-HT_1A receptors, and as an antagonist at 5-HT_2A and 5-HT_2B receptors. Its binding affinity is reported to be high at 5-HT_2B receptors (Ki = 0.58 nM) and 5-HT_1A receptors (Ki = 2.6 nM), moderate at 5-HT_2A receptors (Ki = 18.8 nM), and low at 5-HT_2C receptors (Ki = 155 nM).¹⁵⁵ A flexible-dose clinical trial in adults with ADHD is currently recruiting (NCT04843423).

Centanafadine is a first-in-class norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI) being developed for the treatment of ADHD in children, adolescents, and adults.¹⁵⁶ It has IC₅₀ values of 6 nM for norepinephrine, 38 nM for dopamine, and 83 nM for serotonin transporter reuptake.¹⁵⁷ The NDSRI mechanism may provide a more favorable safety and tolerability profile when compared to the current standard of care. Moreover, the serotonergic activity of centanafadine has been postulated to mitigate treatment-related AEs such as sleep disturbances and changes in appetite.¹⁵⁷ Modulation of serotonin could also assist with associated symptoms of ADHD that are not as well-treated by the current standard of care, including anxiety and depression.¹⁵⁷ To date, the sponsor has completed 9 clinical studies in ADHD, with 2 currently ongoing (NCT05279313 and NCT05428033). Data from two phase 3 studies of the sustained-release formulation conducted in adults with ADHD reported statistically significant improvements in AISRS total scores versus placebo and a low rate of treatment-emergent AEs leading to discontinuation.¹⁵⁸ Two phase 3 studies in pediatric ADHD patients have also been completed, but only topline results have been reported to date; both trials met the primary efficacy endpoint for the higher dose studied, with no new safety concerns identified.¹⁵⁶

Solriamfetol, a dopamine and norepinephrine reuptake inhibitor (DNRI), is indicated to improve wakefulness in adults with excessive daytime sleepiness that is associated with narcolepsy or obstructive sleep apnea.¹⁵⁹ Preclinical data suggest that solriamfetol exhibits agonist activity at the 5-HT_1A receptor¹⁶⁰ as well as trace amine-associated receptor 1 (TAAR1) agonism,¹⁶⁰ which is believed to have several effects on serotonin neurotransmission, including enhancing the potency of 5-HT_1A agonists.¹⁶¹ Agonist activity at TAAR1 was also shown to be involved in serotonergic neurotransmission.^162,163 According to the manufacturer, solriamfetol has low binding affinity for the serotonin transporter (Ki = 81.5 μM) and does not inhibit serotonin reuptake (IC₅₀ > 100 μM).¹⁵⁹ Following the publication of positive data from a dose-optimization pilot study of solriamfetol in 60 adults with ADHD,¹⁶⁴ a phase 3 clinical study was initiated and is currently recruiting (NCT05972044).

Clinical Implications and Future Treatment Expectations

Given that ADHD is one of the most common neuropsychiatric disorders,^11–13,165 and places a high burden on individuals and society, there is a great deal of interest in developing safe and effective treatments. Currently approved therapies include stimulant drugs (MPH and amphetamine derivatives) and a handful of non-stimulants, but concerns relating to efficacy and safety remain.^34–37

The unfavorable outcome rate for drugs intended for ADHD treatment is large, and the bar for evidence robust enough for regulatory approval is set high.¹⁰¹ Nonetheless, there has been considerable progress in the understanding of ADHD neurobiology, and each failure expands our knowledge base and should enable more rational drug development, improved trial procedures, and better optimized dosing in the future.

While the initial focus of drug development was on the catecholamines, norepinephrine and dopamine,^101,166 there is also a large body of evidence indicating a role for the serotonergic system in ADHD. Given the large number of failed trials, it does not appear that serotonergic modulation alone is likely to produce efficacious treatments for ADHD. Instead, it seems likely that altering the balance between monoamine neurotransmission systems is likely to provide the best outcomes, with serotonergic activity complementing effects on norepinephrine and dopamine. Notably, one of the drugs currently in development, centanafadine, is an NDSRI targeting all three of these neurotransmitter systems; based on clinical trial data to date, centanafadine demonstrated clinically meaningful efficacy with a favorable safety and tolerability profile. The use of this and other multimodal agents is expected to expand the pool of available drugs for ADHD, simultaneously providing robust and consistent efficacy alongside a favorable safety profile and lower potential for abuse, and delivering additional benefits with regard to comorbidities (such as sleep, anxiety, and mood).¹⁶⁶

Limitations of this Review

This narrative review does not represent an exhaustive analysis of every compound with serotonergic activity ever tested in ADHD. Instead, it is intended to provide a summary of this often-overlooked area of research, to consider the role of 5-HT in the pathology and treatment of ADHD, and to generate discussion regarding the high unfavorable outcome rate to date. As this study was reliant on information available in the public domain, several compounds for which no data have been made publicly available have been omitted and some supporting sources that were not peer-reviewed have been included.

Conclusions

There is an ever-increasing body of evidence suggesting a role for 5-HT in the neurobiology of ADHD and indicating that modulation of serotonergic neurotransmission and rebalancing of monoamines within the brain may provide an avenue of drug development by which outcomes for patients with ADHD can be improved. In this evidence-based narrative review, many compounds with serotonergic activity that have been studied in ADHD were identified, and pinpointed key reasons for a halt in the developmental process, which include finding the correct dose and selectivity to produce a balance between potency and tolerability. At the current time, clinical studies of several drug candidates with serotonergic activity are ongoing, and it is anticipated that such treatments may positively impact multiple ADHD-associated symptoms, including anxiety and emotional dysregulation, in addition to inattention and hyperactivity.