Expert Opinion on Drug Discovery
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New directions in psychiatric drug development:
promising therapeutics in the pipeline
Linda S. Brady, Sarah H. Lisanby & Joshua A. Gordon
To cite this article: Linda S. Brady, Sarah H. Lisanby & Joshua A. Gordon (2023) New directions
in psychiatric drug development: promising therapeutics in the pipeline, Expert Opinion on
Drug Discovery, 18:8, 835-850, DOI: 10.1080/17460441.2023.2224555
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EXPERT OPINION ON DRUG DISCOVERY
2023, VOL. 18, NO. 8, 835–850
https://doi.org/10.1080/17460441.2023.2224555
REVIEW
New directions in psychiatric drug development: promising therapeutics in the
pipeline
Linda S. Bradya, Sarah H. Lisanbyb and Joshua A. Gordonc
a
Division of Neuroscience and Basic Behavioral Science, National Institute of Mental Health, Bethesda, MD, USA; bDivision of Translational Research,
National Institute of Mental Health, Bethesda,MD, USA; cNational Institute of Mental Health, Bethesda, MD, USA
ABSTRACT
Introduction: Psychiatric disorders are a leading cause of disability worldwide, calling for an urgent
need for new treatments, early detection, early intervention, and precision medicine. Drug discovery
and development in psychiatry continues to expand in new and exciting areas, with several new
medications approved for psychiatric indications by the U.S. Food and Drug Administration (FDA) in
the last 5 years.
Areas covered: In this review, the authors summarize recent new drug approvals and new molecular
mechanisms in Phase 1–3 clinical development for psychiatric disorders. Advances in human geneticsdriven target identification, emergent technologies such as artificial intelligence-enabled drug discov­
ery, digital health technologies, and biomarker tools and strategies for testing novel mechanisms are
highlighted.
Expert opinion: There continues to be a need for research focused on understanding the natural
history, developmental trajectory, and pathophysiology of psychiatric disorders to identify new mole­
cular and circuit-based targets. Looking to the future, a vision of precision psychiatry is emerging,
taking advantage of advances in genetics, digital technology, and multimodal biomarkers to accelerate
the development of next-generation therapies for individuals living with mental illnesses.
1. Introduction
Psychiatric disorders continue to be among the leading causes
of disability worldwide, calling for an urgent need for new
treatments along with early detection, early intervention, and
precision medicine [1]. The psychiatry drug development pipe­
line was last reviewed in 2019 [2]. This review surveys new
molecular targets for compounds in the psychiatric drug
development pipeline, new scientific developments in genet­
ics-driven target identification for drug discovery, and emer­
gent tools and technologies. Together, these advances offer
promise to enable drug discovery and clinical testing of novel
mechanisms that are anticipated to fill the preclinical drug
discovery pipeline in the coming years.
2. New molecular targets (mechanisms of action) in
development
2.1. Recent U.S. Food and Drug Administration drug
approvals
Drug discovery and development in psychiatry continues to
expand into new and exciting areas. In the past 5 years, the
U.S. Food and Drug Administration (FDA) approved 14 new
medications for psychiatric disorder indications [3] (see Table 1).
Of these, four are medications for depression: esketamine nasal
spray (Spravato®), a next-generation rapid-acting adjunctive
ARTICLE HISTORY
Received 25 April 2023
Accepted 8 June 2023
KEYWORDS
biomarkers; bipolar disorder;
major depressive disorder;
post-traumatic stress
disorder; precision
psychiatry; psychiatric
genetics; public–private
partnerships; schizophrenia;
treatment-resistant
depression
medication for adults with treatment-resistant depression (TRD);
intravenous brexanolone (Zulresso®), a first-in-class rapid-acting
medication for postpartum depression (PPD); a fixed-dose combi­
nation of FDA approved drugs dextromethorphan plus bupropion
(AuvelityTM) for the treatment of major depressive disorder (MDD);
and cariprazine (Vraylar®), a second generation atypical antipsy­
chotic, as an adjunctive treatment for MDD.
Five new medications are approved for schizophrenia (SCZ)
or bipolar disorder – a novel mechanism and four new for­
mulations. Lumateperone (Calypta®) is a new treatment for
adults with SCZ and is approved for a second indication, for
treatment of depressive episodes associated with bipolar I or II
disorder in adults either as a monotherapy or as an adjunctive
therapy with lithium or valproate. Dexmedetomide sublingual
film (Igalmi®) is a new orally dissolving formulation approved
for acute agitation associated with SCZ or bipolar I or II
disorder. Three new long-acting injectable (LAI) formulations
utilize novel technologies to deliver risperidone as a biweekly
intramuscular injection (Rykindo®) or aripiprazole (Abilify
Asimtufii®) as a 2-month intramuscular injection to treat
adults with SCZ and as an adjunctive in bipolar I disorder,
and risperidone (UzedyTM) as a 1- or 2-month subcutaneous
injection as a maintenance treatment of SCZ.
Three are medications for attention deficit hyperactivity
disorder (ADHD): a novel fixed-dose combination of central
nervous system (CNS) stimulants serdexmethylphenidate plus
CONTACT Linda S. Brady
lbrady@mail.nih.gov
Division of Neuroscience and Basic Behavioral Science, National Institute of Mental Health, NIMH, 6001
Executive Boulevard, Room 7204, Bethesda MSC 9645
This work was authored as part of the Contributor’s official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance
with 17 USC 105, no copyright protection is available for such works under US Law.
836
L. S. BRADY ET AL.
Article highlights
Drug discovery and development in psychiatry continues to expand
in new and exciting areas, with 15 new medications approved for
psychiatric indications by the U.S. Food and Drug Administration
(FDA) in the last 5 years.
● Six New Drug Applications have been submitted and are under
review by the FDA for major depressive disorder, postpartum depres­
sion, schizophrenia, and post-traumatic stress disorder.
● The psychiatric drug development pipeline contains 118 potential
new medicines with novel mechanisms in Phase 1–3 development by
pharmaceutical companies, including 44 for depression, 29 for schi­
zophrenia, 23 for anxiety disorders, 9 for bipolar disorder, 6 for
attention deficit hyperactivity disorder, and 7 for other neuropsychia­
tric disorder indications.
● Advances in human genetic association studies have identified hun­
dreds of genes and protein-coding variants involved in fundamental
processes of neuronal synaptic biology, differentiation, and transmis­
sion which can be leveraged to discover new therapeutic targets.
● Emergent technologies, including artificial intelligence-enabled drug
discovery, digital health technologies to enable testing of novel
mechanism, and biomarker tools and strategies for disease pheno­
typing, stratification, and staging are enabling the discovery and
development of novel mechanisms.
● A vision of precision psychiatry is emerging, engaging genetics,
digital technology, and multimodal biomarkers to spur the develop­
ment of next-generation therapies for early intervention, maximal
clinical benefit, and reduction of disease burden in individuals living
with mental illnesses.
●
has received Breakthrough Therapy designation for posttraumatic stress disorder (PTSD) with a planned NDA submis­
sion in October 2023 (see Table 2).
2.3. New mechanisms of action in the psychiatric drug
development pipeline
Since the 2019 commentary [2], there has been considerable
progress in psychiatric drug development, with several new
mechanisms moving through the drug development pipeline.
The pipeline contains 118 potential new medicines with novel
mechanisms in Phase 1–3 development by pharmaceutical
companies as of 1 April 2023 based on a curated, advanced
search of ClinicalTrials.gov specifying the following criteria:
psychiatric disorders, interventional studies, recruiting, Phase
1, 2, and 3, and industry-sponsored trials [8]. Table 2 details
active trials for psychiatric indications, with a few recently
completed trials added for compounds that have not yet
moved to the next stage of clinical development. Among
this promising group of drug mechanisms are 44 for depres­
sion, 29 for SCZ, 23 for anxiety disorders, 8 for bipolar disorder,
6 for ADHD, and 7 for other neuropsychiatric disorder indica­
tions, including borderline personality disorder and ASD.
2.3.1. Depression
dexmethylphenidate (Azstarys®); the non-stimulant, extended
release viloxazine (Qelbree®) with low likelihood of abuse and
dependency; and the stimulant, dextroamphetamine patch
(XelstrymTM), a new transdermal formulation approved for
use in adults and children at least 6 years of age.
The urgent need for more effective treatments for mental
illness triggered prioritization of several of these agents. The
FDA granted Breakthrough Therapy designations [4] and
Priority Review for brexanolone and for the fixed-dose combi­
nation of dextromethorphan plus bupropion, Fast Track des­
ignation [5] for lumateperone for the treatment of SCZ, and
both Breakthrough Therapy and Fast Track designations and
Priority Review for esketamine to expedite the development
and review of these novel drugs [6,7]. Several other novel
mechanisms have also received Breakthrough Therapy and
Fast Track designations by the FDA, and the field can look
forward to their further development (see Table 2).
2.2. Recent New Drug Applications
Several promising new medications are in development at the
New Drug Application (NDA) stage (see Table 1). In 2022–2023
to date, six NDAs were submitted to the FDA for psychiatric
indications. A few highlights include: zuranolone, a novel neu­
rosteroid gamma-aminobutyric acid type A (GABAA) receptor
positive allosteric modulator (PAM) for MDD and PPD which
has been granted Priority Review by FDA; KarXT, a novel fixeddose combination of xanomeline plus trospium for treatment
of positive and negative symptoms in SCZ with an NDA sub­
mission planned for mid 2023; and the psychedelic, 3,4-methy­
lenedioxymethamphetamine (MDMA)-assisted therapy which
Many innovative potential medicines are in the development
pipeline for depression, with 15 mechanisms in Phase 1 and 22
mechanisms in Phase 2 trials.
Selected novel mechanisms in Phase 1 include: safety, tol­
erability, and pharmacokinetic studies of the GABAA receptor
compounds SAGE−217 (zuranolone) in development for
pediatric MDD and LYT−300, an oral formulation of allopreg­
nanolone; NMDA receptor modulators BI 1569912, GATE−202
(apistomel); GATE−251 (zelquistinel) which has received Fast
Track designation; JNJ−42847922 (MIN−202, seltorexant), an
orexin−2 receptor antagonist as an adjunctive treatment; and
CVL−354, a kappa opioid receptor antagonist.
New mechanisms in Phase 2 include: ALTO−100, a brainderived neurotrophic factor (BDNF) modulator; BI 1358894 and
XEN1101, ion channel modulators; NBI−1065845, an α-amino-3
-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor
potentiator; NBI−1064846, GPR139, an orphan G-protein
coupled receptor (GPCR) agonist for anhedonia in MDD; and
COMP360 (psilocybin) which has received Breakthrough
Therapy designation by the FDA for TRD.
Novel formulations of ketamine isomers (SLS−002, CLE
−100, PCN−101) and NMDA receptor modulator MIJ821 are
in development for MDD or TRD. And intranasal esketamine
(Spravato®) is in a study to assess safety and efficacy in
pediatric MDD with suicidal ideation. Also in Phase 2, several
formulations of two classes of serotonergic compounds – the
tryptamines, N,N- dimethyltryptamine (DMT) and 5-methoxyN,N-dimethyltryptamine (5-MeO-DMT), both 5-HT receptor
agonists, and psilocybin and psilocin, 5-HT2A receptor ago­
nists, are in development as potential treatments for TRD.
Five novel mechanisms are in Phase 3 development as
adjunctive treatments in MDD. These include: JNJ−42847922
EXPERT OPINION ON DRUG DISCOVERY
837
Table 1. FDA new drug approvals and new drug application submissions for psychiatric disorders.
FDA New Drug Approvals
Mechanism of Action
Indication
esketamine (Spravato )
non-competitive NMDA receptor
adjunctive treatment in TRD
antagonist
Company
Date of Approval
Janssen
March 2019
Pharmaceuticals Inc.
Priority Review
BT and FT
approvals
brexanolone (Zulresso )
neurosteroid GABAA receptor PAM
PPD
Sage Therapeutics Inc. March 2019
Priority Review
BT approval
NME 1
lumateperone (Caplyta )
5-HT2A & D2 receptor antagonist, SERT SCZ
Intra-Cellular Therapies December 2019
inhibitor
Inc.
Standard
Review
FT approval
NME
serdexmethylphenidate plus DA & NE reuptake inhibitor
ADHD
Commave
March 2021
dexmethylphenidate
Therapeutics SA
Standard
(Azstarys )
Review
NME
viloxazine (Qelbree )
selective NE reuptake inhibitor
ADHD
Supernus
April 2021
Pharmaceuticals Inc.
Standard
Review
NME
olanzapine plus
D2 & 5-HT2 receptor antagonist plus a µ SCZ, BP
Alkermes Inc.
May 2021
samidorphan (Lybalvi )
opioid receptor antagonist
Standard
Review
NME
paliperidone palmitate
D2 receptor & 5-HT2A receptor
SCZ
Janssen
September 2021
6-month intramuscular
antagonist
Pharmaceuticals Inc.
Standard
Review
LAI (Invega HafyeraTM)
lumateperone (Caplyta )
5-HT2 & D2 receptor antagonist, SERT
depressive episodes associated with BP I or Intra-Cellular Therapies December 2021
inhibitor
II disorder in adults, as monotherapy
Inc.
Standard
and as adjunctive treatment
Review
dextroamphetamine
CNS stimulant
ADHD in adults and children
Noven Therapeutics
March 2022
TM
(Xelstrym ) transdermal
Standard
patch
Review
dexmedetomide (Igalmi )
a2 adrenergic receptor agonist
acute agitation associated with SCZ or BP BioXcel Therapeutics
April 2022
sublingual film
I or II disorder in adults
Inc.
Standard
Review
®
®
®
®
®
®
®
®
dextromethorphan
hydrobromide plus
bupropion hydrochloride
(AuvelityTM)
cariprazine (Vraylar )
Axsome Therapeutics
Inc.
August 2022
BT designation
Priority Review
D3/D2 & 5-HT1A receptor partial agonist, adjunctive treatment in MDD
5-HT2A & 5-HT2B receptor antagonist
Abbvie Inc.
risperidone ER (Rykindo )
2-week intramuscular LAI
®
D2 receptor & 5-HT2A receptor
antagonist
Luye Pharma Group
risperidone ER (UzedyTM)
D2 receptor & 5-HT2A receptor
antagonist
Teva Pharmaceuticals
and MedinCell
Industries Ltd.
December 2022
Standard
Review
January 2023
Standard
Review
April 2023
Standard
Review
April 2023
Standard
Review
®
1- or 2- month
subcutaneous LAI
aripiprazole (Abilify
Asimtufii )
2-month intramuscular
LAI
NMDA receptor antagonist, sigma 1
receptor agonist plus a DA & NE
reuptake inhibitor, CYP2D6 inhibitor
MDD in adults
SCZ in adults, and as monotherapy or
adjunctive therapy with lithium or
valproate in BP I disorder
SCZ in adults
D2 partial receptor agonist
SCZ in adults, and as maintenance
monotherapy in BP I disorder in adults
H. Lundbeck AS and
Otsuka America
Pharmaceutical, Inc.
New Drug Application
Mechanism of Action
Indication
Company
uranolone
(SAGE−217, BIIB125)
FT and BK designation for
MDD
FT designation for PPD
EXXUATM
(gepirone hydrochloride
ER)
Risvan
(risperidone ISM )
1-month intramuscular
LAI
roluperidone (MIN−101)
neuroactive steroid, GABAA receptor
PAM
MDD, PPD
®
®
®
2
5-HT1A receptor partial agonist & 5-HT2A MDD
receptor antagonist
D2 receptor & 5-HT2A receptor
antagonist
Date of
Submission
Sage Therapeutics Inc. December 2022
and Biogen Inc.
Priority Review
SCZ
5-HT2A antagonist, sigma−2 R antagonist SCZ, negative symptoms
Fabre-Kramer
Pharmaceuticals,
Inc.
Rovi Pharmaceuticals
Laboratories
January 2023
March 20233
Minerva Neurosciences May 2023
(FDA NDA
acceptance)
(Continued )
838
L. S. BRADY ET AL.
Table 1. (Continued).
New Drug Application
Mechanism of Action
KarXT
(xanomeline plus
trospium)
MDMA-assisted therapy
M1/M4 mACh receptor agonist plus
SCZ, psychosis
a peripheral mACh receptor antagonist
5-HT, NE, DA triple reuptake inhibitor
Indication
PTSDa
Company
Karuna
Pharmaceuticals
Multidisciplinary
Association for
Psychedelic Studies
(MAPS)
Date of
Submission
planned mid
2023
planned
October 2023
1
NME is defined by the FDA for the purposes of FDA review as an active moiety that FDA has not previously approved, either as a single ingredient drug or as part of
a combination product.
2
Accepted by the FDA in February 2023 with priority review Prescription Drug User Fee Amendments (PDUFA) date of August 2023.
3
Rovi filed proposed corrections to FDA’s second Complete Response Letter and FDA has issued Rovi a new user fee goal date of July 2023.
Abbreviations: 5-HT, serotonin, 5HT1A, 2A, 2B, serotonin receptor subtypes; ACh, acetylcholine; ADHD, attention-deficit hyperactivity disorder; α2; alpha2
adrenergic receptor subtype; BP, bipolar; BT, Breakthrough Therapy designation by the FDA; CYP2D6, cytochrome P450 2D6; D2, dopamine 2 receptor subtype;
DA, dopamine; ER, extended release; FDA, U.S. Food and Drug Administration; FT, Fast Track designation by the FDA; GABAA, gamma-aminobutyric acid A; ISM, In
Situ Microplants; LAI, long-acting injectable; M1/M4 mACh, muscarinic acetylcholine receptor subtypes; MDD, major depressive disorder; NDA, New Drug
Application; NE, norepinephrine; NMDA, N-methyl-D-aspartate; NME, new molecular entity; PPD, postpartum depression; PAM, positive allosteric modulator;
PTSD, post-traumatic stress disorder; SCZ, schizophrenia; SERT, serotonin transporter; TRD, treatment resistant depression.
(seltorexant) for MDD with insomnia symptoms; aticaprant
and BTRX−335140, kappa opioid receptor antagonists for
MDD with symptoms of anhedonia; REL−1017 (esmethadone),
an NMDA channel blocker that has received Fast Track
Designation by the FDA; and SEP−363856 (ulotaront), a trace
amine-associated receptor 1 (TAAR-1) and serotonin 5-HT1A
receptor agonist that is under development for SCZ and MDD
as an additional indication. Lumateperone (Calypta®) is under
development for a new indication in MDD.
For additional details on novel mechanisms in the drug
development pipeline, see the recent review by Sakurai et al.
on Phase 2/3 trials in depression [9] and GABAA PAM
(GABAkines) in development [10].
2.3.2. Schizophrenia
For SCZ, novel mechanisms in Phase 1 trials include: LB−102
(N-methyl amisulpride), a D2/D3, and 5-HT7 receptor antago­
nist, and CVL−231 (emraclidine), a M4 muscarinic acetylcholine
(mACh) receptor modulator in safety and tolerability studies in
elderly participants. Two long-acting injectable formulations –
iloperidone (Fanapt®) and LY03010 (paliperidone palmitate)
are in Phase 1 development for acute psychosis requiring
hospitalization.
Seven drug candidates are in phase 2 development for
SCZ. Novel mechanisms include: M4 mACh receptor modu­
lators – CVL−231 for psychosis and NBI−1117568 for acute
relapse
requiring
hospitalization;
MK−8189,
a phosphodiesterase PDE10A inhibitor for an acute episode
of SCZ; luvadaxistat, a D-amino acid oxidase (DAAO) inhibi­
tor [11], RL−007 a cholinergic, NMDA, and GABAB receptor
modulator in development for cognitive impairment asso­
ciated with SCZ (CIAS). RG7906 (ralmitaront), a TAAR1 recep­
tor agonist for negative symptoms, was recently terminated.
Thirteen novel drug candidates are in Phase 3 development
for SCZ. Novel mechanisms as stand-alone treatments include:
SEP−353856 (ulotaront), a first-in-class TAAR1 agonist with
5-HT1A receptor agonist activity [12] and KarXT (xanomeline
plus trospium), a M1/M4 mACh receptor agonist plus a perip­
erally-restricted mACh receptor antagonist for positive and
negative symptoms and CIAS [13–15]; and brilaroxazine,
a dopamine-serotonin system stabilizer. And, new mechan­
isms in development as adjunctive treatments are: NaBen®
(SND−13), a DAAO inhibitor for refractory SCZ; BI 425809
(iclepertin), a glycine transporter 1 inhibitor for CIAS [16];
and roluperidone (MIN−101) for negative symptoms.
Also in phase 3, a new LAI formulation of olanzapine, TV−44749
(mcd-TJK), is under development using the same novel extendedrelease technology as in the NDA for risperidone ER (UzedyTM).
Two FDA-approved treatments are in phase 3 extension
studies for adolescents 13–17 years of age with SCZ: olanza­
pine plus samidorphan (Lybalvi®) a fixed-dose combination of
a dopamine D2 receptor and 5-HT2 receptor antagonist plus
a mu opioid receptor antagonist; and cariprazine (Vraylar®).
Pimavanserin (NUPLAZID®), a 5-HT2A receptor antagonist/
inverse agonist, and valbenazine (Ingrezza®), a vesicular
monoamine transporter VMAT2 inhibitor, are in Phase 3 devel­
opment for a new indication for the treatment of negative
symptoms in SCZ. In addition, lumateperone (Calypta®) is in
development for a new indication for prevention of relapse
in SCZ.
Of these new mechanisms, BI 425809 (iclepertin), SEP−363856
(ultotarant), and NaBen® have received Breakthrough Therapy
designations by the FDA for SCZ. For additional details on novel
mechanisms in the drug development pipeline, see the recent
review by Correll et al. of Phase 2 and 3 trials in SCZ [17].
2.3.3. Bipolar disorder
In Phase 2 trials for bipolar disorder, JNJ−55308942, a novel
purinergic ionotropic P2X7 receptor antagonist, is in develop­
ment for major depressive episodes in bipolar I or II disorder
and LYN−005, an extended-release oral formulation of risper­
idone for weekly administration in bipolar I disorder and
schizophrenia.
In Phase 3 development is the novel mechanism: NRX−100/
NRX−101, intravenous ketamine (NRX−100) followed by
a fixed-dose combination of D-cycloserine plus lurasidone
(NRX−101, Cyclurad®) for rapid stabilization of acute suicidal
ideation and behavior in bipolar depression, as well as NRX
−101 alone for maintaining remission of symptoms of depres­
sion, clinical relapse, and suicidal ideation or behavior in
EXPERT OPINION ON DRUG DISCOVERY
839
Table 2. Drugs in industry-sponsored Phase 1–3 clinical trials1.
Category
Mechanism of Action
Depression
SAGE−217 (zuranolone)
GABAA receptor PAM
Phase 1
LYT−300,
GABAA receptor PAM
allopregnanolone, oral
formulation
Phase 1
BI 1569912
NMDA NR2B receptor NAM
Phase 1
Indication
CT.gov
Sage Therapeutics Inc.
and Biogen Inc.
PureTech Health
NCT05655507
adjunctive treatment in MDD
Boehringer Ingelheim
in development for MDD; safety
study in HVs
in development for MDD; safety
study in HVs
Gate Neurosciences Inc.
NCT04937829;
NCT04958252;
NCT04978506
NCT05597241
Gate Neurosciences, Inc.
NCT04981561
NMDA receptor PAM
MDD
Gate Neurosciences, Inc.
NCT03726658;
NCT03586427
orexin−2 receptor antagonist
adjunctive treatment in
adolescent MDD
Janssen Pharmaceutical
Companies
NCT04951609
κ opioid receptor antagonist
in development for MDD; safety
study in HVs
in development for MDD; safety
study in HVs
MDD, single injection in
combination with SSRIs
Cerevel Therapeutics
Holdings, Inc.
Digestome Therapeutics
NCT05138653
Small Pharma Ltd.
NCT05553691
in development for MDD; safety Small Pharma Ltd.
study in HVs; single injection in
combination with SSRIs
in development for TRD; safety
Beckley Psytech
study in HVs
NCT05644093;
NCT05553691
Usona Institute
NCT05698095
5-HT2A receptor agonist
under development for MDD;
safety study in HVs
MDD
Cybin Inc.
NCT05385783
5-HT2A receptor agonist
MDD
Eleusis Therapeutics
NCT05434156
5-HT receptor agonist
TRD, AUD
Beckley Psytech
NCT05660642
5-HT2A receptor agonist
TRD, one prior treatment failure in COMPASS Pathways PLC
current depressive episode
Pharmaceutical
Company
MDD with suicidal ideation with Novartis Pharmaceuticals
intent
Corporation
NCT05733546
Novartis Pharmaceuticals
Corporation
NCT05454410
BDNF modulator
TRD, single injection in addition
to standard of care
antidepressant treatment
MDD
Alto Neuroscience
undisclosed mechanism
MDD
Alto Neuroscience
vasopressin 1b receptor antagonist
MDD
TRPC 4/5 channel inhibitor
MDD
Ancora Bio, Inc. d/b/a
EmbarkNeuro, Inc.
Boehringer Ingelheim
NCT05712187;
NCT05117632
NCT05118750;
NCT05157945
NCT05439603
KCNQ2/3 potassium channel agonist
MDD
5-HT/NE/DA triple uptake inhibitor
MDD
5-HT/NE/DA triple uptake inhibitor
TRD
small molecule, undisclosed mechanism
adjunctive treatment in TRD
AMPA receptor potentiator
adjunctive treatment in MDD
GATE−202 (apimostinel)
Phase 1
GATE−251 (zelquistinel)
Phase 1 completed
FT designation
GATE−251, AGN−24175
(zelquistinel)
Phase 1, 2 completed
FT designation
JNJ−42847922, MIN−202
(seltorexant)
Phase 1
CVL−354
Phase 1
DGX−001
Phase 1
SPL026, N,Ndimethyltryptamine
(DMT), iv
Phase 1
SPL026, DMT, iv or im
Phase 1
NMDA receptor partial agonist
BPL−003, 5-MeO-DMT,
intranasal formulation
Phase 1
5-MeO-DMT, im injection
Phase 1
CYB003, deuterated
psilocybin analog
Phase 1, 2
ELE−101, psilocin, iv
formulation
Phase 1, 2
BPL−003, 5-MeO-DMT,
intranasal formulation
Phase 2
COMP360 (psilocybin)
Phase 2
5-HT receptor agonist
MIJ821 (CAD9271), iv
infusion
Phase 2
MIJ821 (CAD9271), sc
injection
Phase 2
ALTO−100
Phase 2
ALTO−300
Phase 2
ANC−501
Phase 2
BI 1358894
Phase 2
XEN1101
Phase 2
centanafadine (EB−1020)
Phase 2
DB104 (liafensine)
Phase 2
MK−1942
Phase 2
NBI−1065845 (TAK−653)
Phase 2
NMDA NR2B receptor NAM
NMDA receptor PAM
CNS stimulant, via the vagus nerve
5-HT receptor agonist
5-HT receptor agonist
5-HT receptor agonist
NMDA NR2B receptor NAM
pediatric MDD
Company
in development for anxiety,
depression; safety study in HVs
NCT05129865
NCT05121831
NCT05347849
NCT04722666
NCT04521478
Xenon Pharmaceuticals
Inc.
Otsuka Pharmaceutical
Company
Denovo Biopharma LLC
NCT04827901;
NCT05376150
NCT05536414
Merck Sharp & Dohme
LLC
Neurocrine Biosciences,
Inc.
NCT04663321
NCT05113771
NCT05203341
(Continued )
840
L. S. BRADY ET AL.
Table 2. (Continued).
Category
NBI−1065846 (TAK−041)
Phase 2
NV−5138 (SPN820)
Phase 2
Mechanism of Action
GPR139 agonist
Indication
anhedonia in MDD
CT.gov
NCT05165394
MDD
Company
Neurocrine Biosciences,
Inc.
Navitor Pharmaceuticals
Inc., Supernus
Pharmaceuticals Inc.
Tonix Pharmaceuticals Inc.
mTORC1 protein stimulant
adjunctive treatment in TRD
TNX−601, tianeptine
hemioxalate ER
Phase 2
SLS−002, intranasal
racemic ketamine
Phase 2
Spravato , intranasal
esketamine
Phase 2
CLE−100, oral esketamine
Phase 2 completed
PCN−101 (R-ketamine
intravenous infusion)
Phase 2 completed
BTRX−335140 (NMRA
−335140)
Phase 2 completed
κ opioid receptor agonist
non-competitive NMDA receptor antagonist
MDD and suicidality
Seelos Therapeutics, Inc.
NCT04669665
non-competitive NMDA receptor antagonist
MDD with suicidal ideation,
pediatrics
Janssen Pharmaceutical
Companies
NCT03185819
non-competitive NMDA receptor antagonist
adjunctive treatment in MDD
NCT04103892
NMDA receptor antagonist, noncompetitive
NMDA receptor antagonist
TRD
Clexio Biosciences Ltd.,
Tikvah, Israel
Perception Neuroscience
κ opioid receptor antagonist
MDD with symptoms of
anhedonia and anxiety
NCT04221230
SP−624
Phase 2 completed
sirtuin activator
MDD
SEP−363856 (ulotaront)
Phase 2, 3
JNJ−42847922, MIN−202
(seltorexant)
Phase 3
lumateperone (Caplyta )
Phase 3
aticaprant
Phase 3
aticaprant
Phase 3
REL−1017 (esmethadone)
Phase 3
FT designation
COMP360 (psilocybin)
Phase 3
BT designation
Schizophrenia
Risvan , risperidone
ISM monthly im LAI
observational
iloperidone (VYV−6833201) Fanapt LAI
Phase 1
LY03010, paliperidone
palmitate, im monthly
injection LAI
Phase 1
LB−102 (N-methyl
amisulpride)
Phase 1
CVL−231 (emraclidine)
Phase 1
SEP−363856 (ulotaront)
Phase 1
TAAR1 receptor agonist, 5-HT1A receptor
agonist
orexin−2 receptor antagonist
adjunctive treatment in MDD
BlackThorn Therapeutics,
Inc.; collaborator,
Neumora Therapeutics,
Inc.
Arrivo Bioventures LLC
and Sirtsei
Pharmaceuticals, Inc.
Sunovion
Pharmaceuticals, Inc.
Janssen Pharmaceutical
Companies
®
receptor antagonist, D2 receptor
® 5-HT2A
antagonist, SERT inhibitor
®
®
®
SP−624
Phase 1 completed
MT1980
Phase 1 completed
CVL−231 (emraclidine)
Phase 2
NBI−1117568
(HTL0016878)
Phase 2
MK−8189
Phase 2
adjunctive treatment in adults &
elderly MDD with insomnia
symptoms
adjunctive in MDD
NCT05066672
NCT05686408
NCT05414422
NCT04479852
NCT05593029
NCT04533529;
NCT04513912
NCT04985942;
NCT05061706
NCT05518149
NMDA channel blocker
Intra-Cellular Therapies,
Inc.
adjunctive treatment in MDD,
Janssen Pharmaceutical
adults and elderly
Companies
adjunctive treatment in MDD with Janssen Pharmaceutical
moderate to severe anhedonia
Companies
adjunctive treatment in MDD
Relmada Therapeutics
5-HT2A receptor agonist
TRD
COMPASS Pathways PLC
Pharmaceutical
Company
NCT05711940;
NCT05624268
D2 receptor & 5-HT2A receptor antagonist
SCZ, acute relapse requiring
hospitalization
Rovi Pharmaceuticals
Laboratories
NCT05480046
D2 receptor & 5-HT2A receptor antagonist
SCZ
Vanda Pharmaceuticals,
Inc.
NCT04712734
D2 receptor & 5-HT2A receptor antagonist
SCZ, schizoaffective disorder
Luye Pharma
NCT05321602
D2/D3 receptor and 5-HT7 receptor antagonist SCZ
LB Pharmaceuticals, Inc
NCT04187560
M4 mACh receptor modulator
SCZ, elderly patients
NCT05644977
TAAR1 receptor agonist, 5-HT1A receptor
agonist
SCZ, gastric emptying, glucose
regulation, body weight
Cerevel Therapeutics
Holdings, Inc.
Sunovion
Pharmaceuticals, Inc.
sirtuin stimulant
SCZ
novel formulation of an on-market antiinflammatory compound
M4 mACh receptor modulator
neuroinflammatory response in
brain
SCZ/psychosis
M4 mACh receptor agonist
SCZ, acute relapse requiring
hospitalization
PDE10A inhibitor
SCZ, acute episode
κ opioid receptor antagonist
κ opioid receptor antagonist
Arrivo Bioventures/Sirtsei
Pharmaceuticals
Monument Therapeutics
Limited
Cerevel Therapeutics
Holdings, Inc.
Neurocrine Biosciences,
Inc.
Merck Sharp & Dohme
LLC
NCT05455684;
NCT05550532
NCT04855760;
NCT04855747
NCT05402111;
NCT05463770;
NCT05542264;
NCT04510298
NCT05429840
NCT05227703;
NCT05227690
NCT05545111
NCT04624243
(Continued )
EXPERT OPINION ON DRUG DISCOVERY
841
Table 2. (Continued).
Category
luvadaxistat (NBI
−1065844, TAK−831)
Phase 2
RL−007
Phase 2
RG7906 (ralmitaront),
RO6889450
Phase 2 terminated
AVP−786,
deudextromethorphan
analog plus quinidine
Phase 2 completed
evenamide
Phase 2 completed
SEP−363856 (ulotaront)
Phase 3
BT designation
KarXT
(xanomeline plus
trospium)
Phase 3
brilaroxazine (RP5063)
Phase 3
®
NaBen (SND−13)
Phase 2, 3
BT designation
BI 425809 (iclepertin)
Phase 3
BT designation
KarXT
(xanomeline plus
trospium)
Phase 3
pimavanserin
(NUPLAZID )
Phase 3
roluperidone (MIN−101)
Phase 3
Valbenazine (Ingrezza )
Phase 3
olanzapine ER
TV−44749 (mdc-TJK)
2-month subcutaneous
LAI
Phase 3
olanzapine plus
samidorphan
(Lybalvi )
Phase 3
cariprazine (Vraylar )
Phase 3
lumateperone (Caplyta )
Phase 3
Bipolar Disorder
JNJ−55308942
Phase 2
LYN−005, risperidone ER,
once weekly oral
formulation
Phase 2 completed
lumateperone (Caplyta )
Phase 3
SEP−4199 CR, nonracemic amisulpride
Phase 3
iloperidone (VYV−6833201) Fanapt
Phase 3
®
®
®
®
®
Mechanism of Action
DAAO inhibitor
CIAS
Company
Neurocrine Biosciences,
Inc.
CT.gov
NCT05182476
cholinergic, NMDA, & GABAB receptor
modulator
TAAR1 receptor agonist
CIAS
Recognify Life Sciences
NCT05686239
SCZ and schizoaffective disorder/
negative symptoms
Hoffmann-La Roche, Inc.
NCT03669640
NMDA receptor antagonist plus a CYP2D6
inhibitor
SCZ
Avanir Pharmaceuticals
Inc.
NCT02477670
voltage-gated sodium channel blocker
SCZ
Newron Pharmaceuticals
NCT04461119
TAAR1 receptor agonist, 5-HT1A receptor
agonist
SCZ
Sunovion
Pharmaceuticals, Inc.
M1/M4 mACh receptor agonist plus
a peripherally-restricted mACh receptor
antagonist
SCZ, psychosis
Karuna Therapeutics, Inc.
NCT04072354;
NCT04109950;
NCT05628103;
NCT04820309;
NCT05643170
DA−5-HT system stabilizer;
SCZ
Reviva Pharmaceuticals
D2, D3, D4 receptor partial agonist/5-HT1A,
Holdings, Inc.
5-HT2A receptor agonist/5-HT6, 5-HT7,
5-HT2A, 5-HT2B receptor antagonist
DAAO inhibitor
adjunctive treatment in refractory SyneuRx International
SCZ, adolescent/adult
NCT05184335
NCT02261519;
NCT03094429;
NCT01908192
NCT04846868;
NCT04846881;
NCT04860830;
NCT05211947
NCT05145413;
NCT05304767
glyT1 inhibitor
SCZ, cognition & functional
capacity
Boehringer Ingelheim
M1/M4 mACh receptor agonist plus
a peripherally-restricted muscarinic
antagonist
adjunctive treatment in SCZ
Karuna Therapeutics, Inc.
5-HT2A receptor antagonist/inverse agonist,
less so at 5-HT2C receptor
adjunctive treatment in SCZ,
negative symptoms
Acadia Pharmaceuticals
NCT04531982;
NCT03121586
Minerva Neurosciences
NCT03397134
NCT05110157;
NCT05654870
NCT05693935
5-HT2A receptor antagonist, sigma−2 receptor SCZ, negative symptoms
antagonist
VMAT2 inhibitor
SCZ add-on treatment
D2 & 5-HT2 receptor antagonist
SCZ
Neurocrine Biosciences,
Inc.
Teva Pharmaceuticals and
MedinCell Industries
Ltd.
D2 and 5-HT2 receptor antagonist plus µ
opioid receptor antagonist
pediatric SCZ
Alkermes Plc
NCT05303064
D3/D2 & 5-HT1A receptor partial agonist,
5-HT2A & 5-HT2B receptor antagonist
5-HT2A receptor antagonist, D2 receptor
antagonist, SERT inhibitor
pediatric SCZ
AbbVie Inc.
NCT03817502
SCZ, prevention of relapse
Intra-Cellular Therapies,
Inc.
NCT04959032
purinergic P2X7 receptor antagonist, an ATPgated cation channel
D2 receptor & 5-HT2A receptor antagonist
BP I or II disorder, major
depressive episodes
BP I disorder, SCZ
Janssen Pharmaceutical
Companies
Lyndra Therapeutics Inc.
NCT05328297
BP I or II disorder, major
depressive episodes
BP I disorder, major depressive
episode
Intra-Cellular Therapies,
Inc.
Sunovion
Pharmaceuticals, Inc.
NCT04285515
BP, acute manic or mixed
episodes
Vanda Pharmaceuticals,
Inc.
receptor antagonist, D2 receptor
® 5-HT2A
antagonist, SERT inhibitor
®
Indication
5-HT receptor modulator; 5-HT7 receptor
antagonist, less potent D2 receptor
antagonist
D2 receptor & 5-HT2A receptor antagonist
NCT04567524
NCT05227209;
NCT05169710
NCT04819776
(Continued )
842
L. S. BRADY ET AL.
Table 2. (Continued).
Category
NRX−100/NRX−101,
iv ketamine followed
by D-cycloserine plus
lurasidone (Cyclurad )
Phase 3
BT designation
NRX−101, D-cycloserine
plus lurasidone
(Cyclurad )
Phase 3
BT designation
planning2
olanzapine plus
samidorphan
(Lybalvi )
Phase 3
cariprazine (Vraylar )
Phase 3
®
®
®
®
Anxiety Disorders
CVL−865 (darigabat)
Phase 1
Mechanism of Action
NMDA receptor antagonist followed by an
NMDA receptor antagonist plus a
5-HT2A receptor antagonist
Indication
severe BP, ASIB
Company
NRx Pharmaceuticals, Inc.
CT.gov
NCT03396601;
NCT03396068
NMDA receptor antagonist plus a 5-HT2A
receptor antagonist
severe BP depression with ASIB,
maintenance of remission
NRx Pharmaceuticals, Inc.
NCT03396601;
NCT03396068
D2 receptor & 5-HT2 receptor antagonist plus pediatric BP or SCZ
a
µ opioid receptor antagonist
Alkermes Plc.
NCT04987229
D3/D2 receptor & 5-HT1A receptor partial
agonist, 5-HT2A & 5-HT2B receptor
antagonist
pediatric BP I disorder with
depression
AbbVie Inc.
NCT04777357
GABA-A PAM, α2/3/5 receptor subtypes
in development for panic
Cerevel Therapeutics
disorder; CO2 inhalation model
Holdings, Inc.
in HVs
PTSD
Lundbeck
NCT04592536
CB1 receptor NAM
acute anxiety in social anxiety
disorder
Receptor Life Sciences,
Inc.
NCT05429788
TRPC 4/5 channel inhibitor
PTSD
Boehringer Ingelheim
NCT05103657
FAAH inhibitor
PTSD
Jazz Pharmaceuticals, Inc.
NCT05178316
α7 nACh receptor PAM
PTSD
Bionomics Ltd.
NCT04951076
NCT05312151
Lu AG06466
Phase 1
RLS103, CBD inhaled dry
powder
Phase 1
BI 1358894
Phase 2
JZP150
Phase 2
FT designation
BNC210
Phase 2 completed
FT designation
psilocybin
Phase 2
MAGL inhibitor
NCT04597450
5-HT2A receptor agonist
PTSD
RG7314 (balovaptan)
Phase 2
ALTO−100
Phase 2 completed
TNX−102 SL,
cyclobenzaprine
sublingual formulation
Phase 2
CBD, Nantheia ATL5
liquid structure
formulation
Phase 2
MM−120, LSD D-tartrate
Phase 2
FT designation
PH94B nasal spray
Phase 2
FT designation
INP105, POD-OLZ
(olanzapine nasal
spray)
Phase 2
synthetic CBD
Phase 2
VQW−765
Phase 2
BNC210
Phase 2 completed
HB−01
Phase 2 completed
NYX−783
Phase 2, 3
FT designation
SEP−363856
Phase 2, 3
vasopressin 1 receptor antagonist
PTSD
COMPASS Pathways PLC
Pharmaceutical
Company
Hoffman-La Roche Inc.
BDNF modulator
PTSD and/or MDD
Alto Neuroscience
NCT05117632
a centrally-acting muscle relaxant
PTSD
Tonix Pharmaceuticals Inc.
NCT05372887
CB1 receptor NAM
PTSD
ANANDA Scientific
NCT05269459
5-HT2A receptor agonist
GAD
Mind Medicine Inc.
NCT05407064
chemoreceptor cell modulator
social anxiety disorder
VistaGen Therapeutics,
Inc.
NCT04404192
D2 & 5-HT2 receptor antagonist
ASD, acute treatment of agitation Impel Pharmaceuticals,
Inc.
NCT05163717
CB1 receptor NAM
social anxiety disorder
EmpowerPharm Inc.
NCT05600114
α7 nACh receptor agonist
performance anxiety
NCT04800237
α7 nACh receptor NAM
social anxiety disorder
Vanda Pharmaceuticals,
Inc.
Bionomics Ltd.
undisclosed mechanism
panic disorder
Honeybrains Biotech LLC
NCT05071430
NMDA receptor PAM
PTSD
Aptynix Inc.
NCT05181995
TAAR1 receptor agonist, 5-HT1A receptor
agonist
GAD
Sunovion
Pharmaceuticals, Inc.
NCT05729373
NCT05401565
NCT05193409
(Continued )
EXPERT OPINION ON DRUG DISCOVERY
843
Table 2. (Continued).
Category
cariprazine (Vraylar )
Phase 3
BHV−4157 (troriluzole)
Phase 3
MDMA-assisted therapy
(MDMA-AT)
Phase 3
BT designation
ADHD
centanafadine (EB−1020)
Phase 1
ADAIR
(dextroamphetamine)
Phase 1 completed
CX−717
Phase 2
MM−120, LSD D-tartrate
Phase 2
solriamfetol
Phase 2, 3
centanafadine (EB−1020)
Phase 3
centanafadine (EB−1020)
Phase 3
CTx−1301,
dexmethylphenidate
controlled release
formulation
Phase 3
Other Psychiatric
Indications
AVP−786,
deudextromethorphan
analog plus quinidine
Phase 2
L1–79
Phase 2
COMP360 (psilocybin)
Phase 2
Mechanism of Action
D3/D2 & 5-HT1A receptor partial agonist,
5-HT2A & 5-HT2B receptor antagonist
glutamate modulator
Indication
irritability in pediatric ASD
Company
Abbvie Inc.
CT.gov
NCT05439616
adjunctive treatment in OCD
5-HT, NE, DA triple reuptake inhibitor
PTSD
Biohaven Pharmaceutical
Holding Company Ltd.
Multidisciplinary
Association for
Psychedelic Studies
(MAPS)
NCT04693351;
NCT04708834
NCT03537014
5-HT, NE, DA triple reuptake inhibitor
ADHD pediatric safety study
NCT04786730
NE & DA reuptake inhibitor
ADHD
Otsuka Pharmaceutical
Company
Vallon Pharmaceuticals,
Inc.
AMPA receptor modulator
pediatric ADHD
NCT05286762
5-HT2A receptor agonist
ADHD
RespireRx
Pharmaceuticals Inc.
Mind Medicine Inc.
NE & DA reuptake inhibitor
ADHD
Axsome Therapeutics, Inc.
NCT04839562
5-HT, NE, DA triple reuptake inhibitor
ADHD, adolescents
5-HT, NE, DA triple reuptake inhibitor
ADHD, children
NCT05257265;
NCT05279313
NCT05428033
DA & NE reuptake inhibitor
ADHD
Otsuka Pharmaceutical
Company
Otsuka Pharmaceutical
Company
Cingulate Therapeutics
NMDA receptor antagonist plus a CYP2D6
inhibitor
TBI/neurobehavioral inhibition
Avanir Pharmaceuticals
Inc.
NCT03095066
tyrosine hydroxylase inhibitor
ASD
NCT05067582
5-HT2A receptor agonist
anorexia nervosa
TRYP−0082 (psilocybin)
Phase 2
lumateperone (Caplyta )
Phase 2
BI 1358894
Phase 2 completed
SXC−2023, SLC7A11
protein stimulant
Phase 2 completed
5-HT2A receptor agonist
binge eating disorder
Yamo Pharmaceuticals
LLC
COMPASS Pathways PLC
Pharmaceutical
Company
TRYP Therapeutics Inc.
Intra-Cellular Therapies,
Inc.
Boehringer Ingelheim
NCT05356013
Promentis
Pharmaceuticals, Inc.
NCT03797521
®
receptor antagonist, D2 receptor
® 5-HT2A
antagonist, SERT inhibitor
borderline personality disorder
TRPC 4/5 inhibitor
borderline personality disorder
cystine/glutamate antiporter activator
trichotillomania in adults
NCT04647903
NCT05200936
NCT05631626
NCT05481736
NCT05035927
NCT04566601
1
The data in Table 1 were assembled from a search of Phase 1–3 trials listed as active and recruiting for psychiatric indications in ClinicalTrials.gov as of April 1, 2023.
At a February 13, 2023 meeting, the FDA encouraged NRx to request a BT Planning meeting for NRX−101 to consider enlarging the clinical development program
to allow for chronic treatment of patients with bipolar depression and intermittent suicidality.
Abbreviations: 5-HT, serotonin; 5-HT1A, 1B, 2A, 2B, 6, 7, serotonin receptor subtypes; ACh, acetylcholine; ADHD, attention-deficit hyperactivity disorder; α2, alpha2
adrenergic receptor subtype; α7 nACh, alpha7 nicotinic acetylcholine receptor subtype; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AUD,
alcohol use disorder; ASIB, acute suicidal ideation and behavior; BDNF, brain-derived neurotrophic factor; BP, bipolar; BT, Breakthrough Therapy designation by the
FDA; CB1, cannabinoid 1 receptor subtype; CB1, cannabinoid receptor subtype; CBD, cannabidiol; CIAS, cognitive impairment associated with schizophrenia;
CYP2D6, cytochrome P450 2D6; DMT, N,N-dimethyltryptamine; D2, dopamine 2 receptor subtype; DA, dopamine; DAAO, D-amino acid oxidase; FAAH, fatty acid
amide hydrolase; FDA, U.S. Food and Drug Administration; FT, Fast Track designation by the FDA; GABAA, gamma-aminobutyric acid A; GABAA, gammaaminobutyric acid type A; GPCR, G-protein coupled receptor; glyT1, glycine transporter 1; HVs, healthy volunteers; 5-HT, 5-hydroxytryptamine (serotonin); KCNQ2/
3, voltage-gated M-type potassium channel subtypes; ISM, in situ microparticles; im, intramuscular, iv, intravenous; LAI, long-acting injectable; LSD, lysergic acid
diethylamide; M1/M4 mACh, muscarinic acetylcholine receptor subtypes; MAGL, monoacylglycerol lipase; MDD, major depressive disorder; MDMA, 3,4-methyle­
nedioxymethamphetamine; 5-MeO-DMT, 5-methoxy-N,N-dimethyltryptamine; mTORC1, mammalian target of rapamycin complex 1; NAM, negative allosteric
modulator; NE, norepinephrine; NMDA, N-methyl-D-aspartate; NR2B, subunit of the NMDA receptor; OCD, obsessive-compulsive disorder; P2X7, purinergic receptor
antagonist; PPD, postpartum depression; PAM, positive allosteric modulator; PDE, phosphodiesterase; PTSD, post-traumatic stress disorder; sc, subcutaneous; SCZ,
schizophrenia; SERT, serotonin transporter; SLC7A11, solute carrier family 7 member 11; SSRI, selective serotonin reuptake inhibitor; TAAR1, trace amine-associated
receptor 1; TRD, treatment resistant depression; TRPC 4/5, transient receptor potential channel 4/5 subtypes; VMAT2, vesicular monoamine transporter 2
2
bipolar depression. The NRX−100/NRX−101 combination has
received Breakthrough Therapy and Fast Track designations by
the FDA for treatment of severe bipolar disorder and acute
suicidality and behavior. And at a recent FDA meeting, the
FDA encouraged a BT Planning Meeting for NRX−101 to
consider enlarging the clinical development program to
allow for chronic treatment of patients with bipolar depression
and intermittent suicidality [18].
In addition, amisulpride (SEP−4199 CR), a 5-HT receptor
modulator, is in Phase 3 trials for major depressive episodes
844
L. S. BRADY ET AL.
in bipolar disorder and iloperidone (Fanapt®) is in develop­
ment as a LAI formulation for acute manic or mixed episodes.
Lumateperone (Caplyta®) is in development as a new indica­
tion for major depressive episodes in bipolar disorder and olan­
zapine plus samidorphan (Lybalvi®) and cariprazine (Vraylar®)
are in extension studies for adolescents 10–17 years of age.
2.3.4. Anxiety disorders
For anxiety disorders, selected novel mechanism in Phase 1–3
development for PTSD are highlighted. Lu AG06466, a novel
monoacylglycerol lipase (MAGL) inhibitor, is in Phase 1 trials.
Eight mechanisms are in Phase 2 development. Among these:
JZP150, a fatty acid amide hydrolase (FAAH) inhibitor and
BNC210, an /7 nACh receptor NAM, both of which have
received Fast Track designations from FDA; BI 1358894, an
ion channel inhibitor that is also in development for depres­
sion; and psilocybin, a 5-HT2A receptor agonist. Two novel
formulations are in Phase 2 development: TNX−102 SL,
a sublingual formulation of cyclobenzaprine; and NantheiaTM
ATL5, an oral formulation of cannabidiol. And in Phase 3
development, MDMA-assisted therapy, which has received
Breakthrough Therapy designation.
2.3.5. ADHD and other neuropsychiatric disorders
Five mechanisms are in development for ADHD. In Phase 1
trials: a pediatric safety study of centanafadine (EB−1020),
a new 5-HT-norepinephrine (NE)-DA triple reuptake inhibitor;
and ADAIR (dextroamphetamine), an NE and DA reuptake
inhibitor. Three drug candidates are in Phase 2 testing: CX
−717, an AMPA receptor modulator; MM−120, LSD D-tartrate,
which is also in development for generalized anxiety disorder;
and solriamfetol, a NE and DA reuptake inhibitor. And in Phase
3 trials: centanafadine safety and efficacy in children and
adults; and CTx−1301, a controlled release formulation of
dexmethylphenidate. Six mechanisms are in Phase 2 develop­
ment for other psychiatric disorders (see Table 2).
With the diversity of novel mechanisms entering Phase 1–3
testing, there are many opportunities for transformative treat­
ments in the near future. For additional mechanisms in devel­
opment beyond the list sourced from www.clinicaltrials.gov in
this commentary, see the 2023 report from the Pharmaceutical
Research and Manufacturers of America (PhRMA) [19].
3. New scientific developments
3.1. Genetics-driven target identification for drug
discovery
Retrospective analyses of drugs in clinical development
have shown that drug mechanisms with supporting
human genetic data for their intended indication are more
than twice as likely to be approved as drugs that lacked
such validation [20–22]. Accordingly, psychiatric genetics
research holds promise for identifying novel targets for
accelerating drug discovery. In the last decade, genomewide association studies (GWAS) in large-scale populationbased cohorts, driven by large international collaborations
such as the Psychiatric Genomics [23], the CommonMind
[24], and the Schizophrenia Exome Sequencing Meta-
Analysis (SCHEMA) [25] Consortia, have provided a rich
resource of human genetic evidence to support target
selection for psychiatric drug discovery. Recent GWAS in
SCZ [26], BP disorder [27], and MDD [28] have identified
hundreds of genes and protein-coding variants which are
involved in fundamental processes of synaptic biology,
including synaptic organization, differentiation, and trans­
mission resulting in an increased understanding of the role
of gene function and regulation in psychiatric disorders
which can be leveraged to discover new therapeutic targets
[29, 30]. To date, however, these findings have not yet been
translated into drugs or even drug targets. The vast number
of genetic associations, each of which confers a small
amount of risk, have made it challenging to map these
risk loci onto specific genes and pathways.
Two important gaps remain if these challenges are to be
overcome. The first relates to the lack of diversity in genetic
samples. Nearly all large-scale human genetics studies have
been based on cohorts that are chiefly composed of indivi­
duals of European ancestry. Such studies have limited general­
izability of the findings to non-European populations. To
address this gap, the National Institute of Mental Health
(NIMH) established the Ancestral Populations Network to
accelerate gene discovery and brain mapping for psychiatric
disorders in cohorts of non-European ancestry to improve the
mapping of genetic risk, enhance the equitable application of
genetic knowledge, and insure mental health equity for min­
oritized and underserved populations in the U.S. and to
increase population diversity [31]. A consortium consisting of
seven funded projects is focused on diversifying gene discov­
ery in cohorts across more than 25 U.S. and international sites
in North and South America, Africa, and Asia.
A second key step to move from gene variants that confer risk
for psychiatric disorders to therapeutic targets is understanding
where, when, and how the genes may impact brain function to
lead to pathophysiology. NIMH has established the Scalable and
Systematic
Neurobiology
of
Psychiatric
and
Neurodevelopmental Disorder Risk Genes (SSPsyGene)
Consortium [32] comprised of four Assay and Data Generation
Centers and a Data Resource Center. The SSPsyGene Consortium
plans to characterize the function of 100–150 high-confidence
risk genes in neurodevelopmental and neuropsychiatric disor­
ders in an array of molecular, cellular, and systems-level func­
tional assays, including induced pluripotent stem cells (iPSCs)
[33], organoids [34], and model organisms, to identify key pro­
teins/hubs, molecular mechanisms, and pathways disrupted by
mental illness risk genes [35]. The data resulting from this con­
sortia effort aims to provide a comprehensive understanding of
the biological pathways and processes disrupted by mental ill­
ness risk genes and lay the foundation for delivering a set of
novel validated targets to feed into the drug discovery pipeline
for psychiatric disorders.
3.2. Consortia efforts and resources to advance
genomics and proteomics targets
Examples of human brain cell atlas efforts that support target
validation include: the National Institutes of Health (NIH) Brain
Research Through Advancing Innovative Neurotechnologies®
EXPERT OPINION ON DRUG DISCOVERY
(BRAIN) Initiative [36] and the PsychENCODE Consortium. The
BRAIN Initiative® is using cutting-edge imaging and single-cell
analysis methods to generate detailed multi-omic data refer­
ence maps from postmortem brains of neurotypical subjects.
These data will detail the full panoply of brain cell types and
spatial locations as a framework for the study of brain dis­
orders. The data will be available from adult and prenatal
human brain, as well as mouse and non-human primate
brains, and shared through a searchable web portal [37]. The
PsycheENCODE Consortium [38] is cataloging gene expression
networks and genomic regulatory elements in postmortem
brains from individuals with a variety of psychiatric disorders
[39]. Comparing the pathological and control conditions and
comparing the genetic and gene expression characteristics of
specific disorders has the potential to further the understand­
ing of how genetic risk maps onto brain function and
dysfunction.
4. Emergent tools and technologies to enable drug
discovery and clinical testing of novel mechanisms
4.1. Artificial intelligence-enabled drug discovery
Artificial intelligence (AI) is a promising approach for advan­
cing the small-molecule drug discovery and development
pipeline through the integration of machine learning algo­
rithms to identify potential drug candidates, to predict their
effectiveness and safety, and to optimize their design. AI and
machine learning (ML) approaches have increasingly been
applied for computer-aided drug design (CADD) at all stages
of drug discovery from target identification and validation,
prediction of molecular structure and function, and compound
screening and optimization [40]. A recent analysis of the pipe­
line composition of 24 AI drug discovery companies indicated
that many of the disclosed AI discovery programs are focused
in CNS therapeutic areas, with more than 60% of the targets
focused on GPCRs and kinases [41]. One of the greatest hopes
for AI-enabled drug discovery is an acceleration of drug dis­
covery timelines including more rapid target identification and
validation and more rapid cycles of molecule design and
optimization. In CNS, a few AI-derived small molecules target­
ing serotonin receptors have been reported to have entered
into Phase 1 testing within less than 12 months from initial
screening to the end of preclinical testing based on the cen­
taur chemist AI powered platform, below the global industry
average of 4–6 years. One of these – DSP−0038, a high
potency antagonist for the 5-HT2A receptor and agonist for
the 5-HT1A receptor – is currently in Phase 1 testing for
improved antipsychotic effects against psychosis associated
with Alzheimer’s disease, as well as improvements in beha­
vioral and psychological symptoms of dementia including
agitation, aggression, anxiety, and depression [42]. For
a recent review of AI in drug discovery, see [43].
845
promise for accelerating innovation, reducing clinical trial
duration, and minimizing risk in medicines development.
DHTs use computing platforms, connectivity, software, and
sensors for healthcare applications. A digital biomarker
builds on the definition of a biomarker as defined in the
Biomarkers, EndpointS, and other Tools (BEST) glossary
developed by the FDA and National Institutes of Health
(NIH) NIH Biomarker Working Group [44], and is defined as
a ‘characteristic or set of characteristics, collected from
digital health technologies, that is measured as an indicator
of normal biological processes, pathogenic processes, or
responses to an exposure or intervention, including thera­
peutic interventions’ [45]. In the definition, the use of ‘char­
acteristic or set of characteristics’ stems from the ability to
derive one or more biomarkers from one or more DHTs
simultaneously.
Examples of DHTs that are increasingly being integrated
into both clinical research and clinical trials in psychiatry
include wearable devices that collect daily actigraphy, sleep,
geolocation data, smartphone applications that collect
momentary assessments via surveys [46], and smartphone
applications that collect speech frequency and duration to
extract health-relevant biosignals [47]. These technologies
are of interest because they provide high-frequency patientgenerated assessments that are noninvasive and scalable and
have the potential to be used as novel or adjunctive endpoints
to traditional clinician-rated endpoints in clinical trials.
Examples of recent studies using DHTs include the
Remote Assessment of Disease and Relapse-Major
Depressive Disorder (RADAR-MDD) study of symptom
change and relapse in MDD [48], the RADMIS trial to inves­
tigate the effect of smartphone-based monitoring on the
rate and duration of readmissions in unipolar and bipolar
disorder [49, 50] and automated speech and language ana­
lysis to characterize mental health status and social skills
and functional competency in SCZ and bipolar disorder [51].
A recent review highlights the use of digital phenotyping to
aid in the diagnosis of major depressive episodes across
MDD, bipolar disorder, and its presentation in the presence
of psychological trauma or PTSD [52].
Several recent Foundation for the National Institutes of
Health (FNIH)-convened workshops have presented case stu­
dies and discussed opportunities and challenges around the
use of digital measures in clinical trials with case studies in
psychiatric disorders [53]. The FDA has recently released
a draft guidance for the use of DHTs – systems that make
use of computing platforms together with sensors and/or soft­
ware that are connected to the platform and used for healthrelated purposes – to aid in remote clinical data acquisition
[54], and in March 2023, it released a framework to guide the
use of DHTs in drug development and medical product devel­
opment [55].
4.2. Digital health technology tools to enable testing of
novel mechanisms
4.3. Biomarker tools and strategies for disease
phenotyping, stratification, and staging
Digital health technology (DHT) tools are an emerging suite
of technologies and smartphone-based applications with
Biomarkers have the potential to greatly enhance the testing
of novel drug candidates by providing quantitative measures
846
L. S. BRADY ET AL.
of disease presence and status, measures of response to treat­
ment, and patient selection and stratification in clinical trials
[56]. The discovery, validation, qualification, and use of bio­
markers, and their adaptation to a variety of drug develop­
ment and regulatory decision-making purposes are all areas of
tremendous interest and need [57, 58]. While individual bio­
markers such as positron emission tomography (PET) imaging
have had an impact in understanding the pharmacokinetic
principles of exposure at the site of action, target binding,
and expression of functional pharmacologic activity in earlystage trials [59], the ability of individual biomarkers to reflect
disease susceptibility or guide therapeutic decision-making in
psychiatric disorders remains an unmet need.
Multimodal (multicomponent) biomarkers may be a better
strategy to capture the complexity of psychiatric disorders,
which are heterogeneous and diagnosed on the basis of
clinician-rated symptoms and behavior and offer the potential
for improving diagnosis and identifying individuals in presymptomatic stages of the illness, in addition to predicting,
monitoring, and guiding treatment development. For more
information on multimodal biomarkers, see the National
Academies’ workshop on Multimodal Biomarkers for CNS
Disorders: Development, Integration, and Clinical Utility [60]
and the FDA workshop on the Identification of Concepts and
Terminology for Multi-Component Biomarkers [61].
Consortia are playing an important role in developing
standardized instrumentation, data collection methods, and
data processing and analysis pipelines for translational bio­
markers (imaging, neurophysiological, and other measures) to
enable the collection of high-quality data that is reliable and
scalable for broader use in drug discovery and development
[62]. The industry-led Event Related Potential (ERP) Biomarker
Qualification Consortium is an example of a pre-competitive
effort among industry, academia, and regulators to ensure
that robust and reliable ERP and quantitative electroencepha­
lography (qEEG) biomarkers can be effectively collected in
target clinical populations, such as patients with schizophre­
nia, thus ensuring scalability and consistency across studies
[63]. The first study from the ERP Consortium established test–
retest reliability for ERP qEEG measures, a validated, auto­
mated data analysis pipeline, and normative ERP/qEEG data­
sets in schizophrenia subjects and matched healthy
volunteers [64].
The Accelerating Medicines Partnership® in Schizophrenia
(AMP® SCZ) is an example of a public-private consortia effort
aiming to validate a multimodal biomarker and clinical assess­
ment strategy to better define and predict the trajectory of
individuals at clinical high risk for psychosis (CHR) to enable
a path for testing novel pharmacologic treatments for early
intervention in schizophrenia [65, 66]. Biomarkers include neu­
roimaging, event-related electrophysiological measures,
a computerized cognitive battery, genetic and fluid biomarkers,
daily digital assessments (actigraphy, sleep, geolocation, and
smartphone surveys), speech, and clinical measures including
attenuated positive symptoms and core symptom domains.
Feature extraction across modalities will be used to integrate
biomarker data and develop algorithms that predict the trajec­
tories and clinical endpoints for conversion to first episode psy­
chosis, remission of the CHR, and non-conversion/non-remission
characterized by cognitive and functional impairment. The suc­
cess of consortia efforts such as these may provide a set of
translational biomarkers that can be used as standardized drug
development tools in clinical trials to quantify pharmacodynamic
effects of novel mechanisms. And some of these tools may also
have potential uses as objective biomarker-based endpoints to
assess potential clinical benefit in early-stage trials to enable
decision-making about further clinical development.
5. Expert opinion
The progress and promise detailed above represent a partial
rejuvenation of interest in psychopharmacology by academia
and the pharmaceutical industry alike, fueled in part by
advances in genetics, technology, and computation as noted.
There continues to be a need for research focused on under­
standing the natural history, developmental trajectory, and
pathophysiology of psychiatric disorders to identify new mole­
cular and circuit-based targets for early intervention, maximal
clinical benefit, and reduction of disease burden in individuals
living with mental illnesses. In considering the future of pro­
gress, a vision of precision psychiatry emerges, engaging
genetics, digital technology, and multimodal biomarkers har­
nessing next-generation therapies.
5.1. Leveraging genetics for next-generation therapies
The tremendous progress in psychiatric genetics is inspiring
novel mechanistic approaches toward identifying targets for
treatment (and even early intervention and prevention) for
psychiatric disorders like schizophrenia. Some of this progress
is fueled by resources and technologies developed through
the BRAIN Initiative that sit at the intersection of engineering
and neuroscience. But the prospects of neuroengineering are
not limited to fostering the development of novel small mole­
cule drugs. The tools being developed by the BRAIN Initiative
that permit monitoring and modulating specific cell types in
the brain could potentially be harnessed for therapeutic use.
Already, gene therapies are available for CNS disorders [67].
Building off of such technologies, one can imagine therapeutic
strategies for single-gene causes of psychiatric disorders like
syndromal schizophrenia or neurodevelopmental disorders.
Further technological advances are necessary, in addition to
clinical studies that point to where and when interventions
should be targeted, as well as biomarkers and clinical outcome
measures that will help evaluate efficacy.
5.2. Digital health technology tools, digital biomarkers,
and digital phenotyping
Digital technologies may facilitate earlier detection of symp­
toms, monitor real-time changes in symptoms at the indivi­
dual level, and aid in identifying clinically meaningful benefit
of novel interventions in clinical trials. This could lead to
smaller, more efficient clinical trials, reducing the burden on
patients, and bringing medicines to patients faster. Unlike
conventional clinical rating scales, digital technologies offer
objective measures with high temporal resolution acquired in
EXPERT OPINION ON DRUG DISCOVERY
the home and in the community settings. This is a significant
advantage especially in the development of rapid-acting treat­
ments since they allow for much more frequent readouts.
Speech sampling has proven particularly promising, and its
ease of collection and low cost make it scalable. Passive sen­
sing is a particular advantage in individuals who lack insight,
and/or may be disincentivized to report accurately (e.g., emer­
ging psychosis, mania, thoughts of self-harm, etc.). Digitally
derived data may reveal heterogeneity that may help to
explain individual variability in treatment response. Digital
technologies offer new approaches to predict relapse, giving
early warning to clinicians about patients in need of assess­
ment and intervention [68]. The ability to predict clinical out­
comes at an individual level will enable drug developers to
enrich their samples for persons most likely to develop the
clinical condition being targeted by the drug, thereby enhan­
cing signal and lowering needed sample size. For example, the
Advancing Understanding of Recovery After Trauma (AURORA)
study found that wrist-wearable device biomarkers predicted
a range of clinical outcomes following trauma [69]. Such mea­
sures can be used to select the subset of patients most likely
to develop a specific outcome in trials of drugs to prevent the
onset of that outcome. It will be important to demonstrate the
validity of digitally derived biomarkers and phenotypes for
such applications in drug development.
5.3. Multimodal biomarker strategies
A multimodal approach to biomarker discovery presents the
appeal of incorporating multiple streams of data that may
capture different domains of function and pathophysiological
phenomena. Large-scale efforts supported by NIMH to dis­
cover multimodal biomarkers include the aforementioned
AMP SCZ and AURORA studies. While the multimodal
approach is highly promising, it also presents a number of
challenges with respect to reliability, reproducibility, and valid­
ity. Collecting multiple data types longitudinally over time in
large samples across multiple sites is resource intensive and
requires rigorous standardization of collection methods and
devices, data quality monitoring, and capture of various types
of meta-data that will be needed to inform the analysis.
Curating and archiving such multimodal data in a manner
that will enable advanced data sciences approaches (e.g., AI
and machine language) to identify multimodal biomarkers are
additional challenges, as is the development of data stan­
dards, data dictionaries and other tools that will enable the
data to be maximally useful. Principled approaches to data
science, including measures to prevent over-fitting (separate
study set, test set, and independent validation set), will be key
to realizing the potential of the multimodal biomarker strat­
egy. New data science approaches, and software platforms,
may be needed to achieve multimodal data fusion and sup­
port further studies in this arena.
5.4. Leveraging precision medicine to transform
therapeutics
Data-driven machine learning analyses can be applied to
identify disease-relevant biotypes, predict individual symptom
847
profiles, and guide decision-making for personalized therapeu­
tic interventions. A framework for precision psychiatry built on
multimodal biomarkers, systems medicine, digital health tech­
nologies, and data science approaches was highlighted in
a recent review using Alzheimer’s disease as a case study
[70]. Tools such as electroencephalography, neuroimaging,
digital and other quantitative behavioral testing can be com­
bined with algorithmic approaches that enable stratification of
patients based on likelihood of response to a given drug or
treatment modality. A concept presented at a recent National
Advisory Mental Health Council meeting lays out an NIMH
strategy to validate tools (behavioral, physiological, and biolo­
gical) to predict individual response among two or more
existing therapeutics for depression [71] and an NIH notice
of a funding opportunity has been issued [72].
We are optimistic that many of the molecular targets in the
psychiatric drug development pipeline will join the armamen­
tarium of new treatments for mental illnesses and that new
targets emerging from the field of neuroscience and genetics
will enter into drug discovery and development over the next
five to ten years, yielding better treatments for patients. As
new technologies and multimodal biomarker efforts are
deployed to define disease phenotypes and early stages of
illness for earlier intervention with pharmacological and psy­
chosocial treatments, it will be possible in the not-too-distant
future to achieve better clinical outcomes for individuals with
psychiatric disorders.
Funding
This manuscript has not been funded.
Declaration of interest
All authors are employees of the National Institute of Mental Health
(NIMH). SH Lisanby additionally is an inventor of patents and has patent
applications on electrical and magnetic brain stimulation therapy systems
held by the National Institutes of Health and Columbia University and
does not receive royalties. The authors have no other relevant affiliations
or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials dis­
cussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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