List of investigational antidepressants
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This is a list of investigational antidepressants, or
antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common Side effect, side-effects of antidepressants include Xerostomia, dry mouth, weig ...
s that are currently under development for clinical use in the treatment of
mood disorder A mood disorder, also known as an affective disorder, is any of a group of conditions of mental and behavioral disorder where a disturbance in the person's mood is the main underlying feature. The classification is in the '' Diagnostic and St ...
s but are not yet approved. ''Chemical/generic names are listed first, with developmental code names, synonyms, and brand names in parentheses.'' All drugs listed are specifically under development for
major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...
(MDD) and/or
treatment-resistant depression Treatment-resistant depression is a term used in psychiatry to describe people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time. Definitions of treatment- ...
(TRD) unless noted otherwise. Other forms of depression may include bipolar depression and
postpartum depression Postpartum depression (PPD), also called postnatal depression, is a type of mood disorder associated with childbirth, which can affect both sexes. Symptoms may include extreme sadness, low energy, anxiety, crying episodes, irritability, and cha ...
.


Glutamatergics


NMDA receptor modulators

* 4-Chlorokynurenine (AV-101) –
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and ...
glycine site The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and ...
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...
*
Apimostinel __NOTOC__ Apimostinel (GATE-202, formerly NRX-1074) is an investigational antidepressant, acting as a novel and selective modulator of the NMDA receptor. It is currently under development for the acute treatment of major depressive disorder (MDD) ...
(GATE-202, NRX-1074) – NMDA receptor
modulator In electronics and telecommunications, modulation is the process of varying one or more properties of a periodic waveform, called the ''carrier signal'', with a separate signal called the ''modulation signal'' that typically contains informatio ...
*
Arketamine Arketamine (developmental code names PCN-101, HR-071603), also known as (''R'')-ketamine or (''R'')-(−)-ketamine, is the (''R'')-(−) enantiomer of ketamine. Similarly to racemic ketamine and esketamine, the ''S''(+) enantiomer of k ...
(PCN-101, HR-071603) – unknown mechanism of action, indirect
AMPA receptor The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic transmembrane receptor for glutamate ( iGluR) that mediates fast synaptic transmission in the cent ...
activator * Esketamine (Esketamine DPI, Falkieri, PG061) – non-competitive NMDA receptor antagonist – approved for TRD, specifically under development for bipolar depression and "depressive disorders

* Esmethadone (dextromethadone; REL-1017) – NMDA receptor antagonist open channel blocker *
Ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppress ...
(PMI-100, PMI-150, R-107, SHX-001, SLS-002; TUR-002) – non-competitive NMDA receptor antagoni

https://adisinsight.springer.com/drugs/80005233

* MIJ-821 – NMDA receptor subunit 2B (NR2B) negative allosteric modulatorbr>
*
Rislenemdaz Rislenemdaz (developmental code names CERC-301, MK-0657) is an orally-active, selective NMDA receptor subunit 2B (NR2B) antagonist which is under development by Cerecor in the United States as an adjunctive therapy for treatment-resistant depre ...
(CERC-301, MK-0657) – NMDA receptor NR2B antagonist


AMPA receptor modulators

* TAK-653 (NBI-1065845) –
AMPA receptor The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic transmembrane receptor for glutamate ( iGluR) that mediates fast synaptic transmission in the cent ...
positive allosteric modulatorbr>


Monoaminergics


Monoamine reuptake inhibitors

* OPC-64005 – serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI

* PDC-1421 (BLI-1005) –
norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and ep ...
(NRI) *
Toludesvenlafaxine Toludesvenlafaxine (former developmental code names LY03005, LPM570065), also known as ansofaxine or as 4-methylbenzoate desvenlafaxine, is a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) which is under development by Luye Phar ...
(ansofaxine; LY03005, LPM570065) – SNDRI


Monoamine reuptake inhibitors and receptor modulators

*
Hypidone Hypidone (developmental code name YL-0919) is an investigational serotonergic antidepressant which is under development for the treatment of major depressive disorder. It acts as a serotonin reuptake inhibitor, 5-HT1A receptor partial agonist, a ...
(YL-0919) – SRI, 5-HT1A receptor partial agonist, and 5-HT6 receptor agonis

* TGBA01AD (FKB01MD) –
serotonin reuptake inhibitor A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the action of the serotonin transporter (SERT). This in turn leads to incre ...
(SRI), 5-HT1A and 5-HT1D receptor
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...
, and 5-HT2 receptor antagonist * Vortioxetine (Trintellix) – SRI, 5-HT1A receptor agonist, 5-HT1B receptor partial agonist, 5-HT1D, 5-HT3, and 5-HT7 receptor antagonist – approved for MDD, under development for bipolar depressio


Monoamine releasing agents

*
Lisdexamfetamine Lisdexamfetamine, sold under the brand name Vyvanse among others, is a stimulant medication that is mainly used to treat attention deficit hyperactivity disorder (ADHD) in people over the age of five as well as moderate-to-severe binge eatin ...
(Elvanse, LDX, NRP-104, S-877489, SHP-489, SPD-489, Tyvense, Venvanse, Vyvanse) – norepinephrine–dopamine releasing agent (NDRA

* Midomafetamine (MDMA; ecstasy) – serotonin–norepinephrine–dopamine releasing agent (SNDRA


Monoamine receptor modulators

* Aramisulpride/esamisulpride (85:15 ratio) (SEP-4199) – 5-HT7 receptor antagonist (aramisulpride) and D2 and D3 receptor antagonist (esamisulpride) – specifically under development for the treatment of bipolar depression *
Gepirone Gepirone is an antidepressant and anxiolytic drug of the azapirone group that was synthesized by Bristol-Myers Squibb in 1986 and has been under development for the treatment of depression but has yet to be marketed. It has been under developmen ...
(TGFK07AD; Travivo) – 5-HT1A receptor partial agonist * Pramipexole (CTC-501, CTC-413) – D2, D3, and D4 receptor agonist *
Psilocybin Psilocybin ( , ) is a naturally occurring psychedelic prodrug compound produced by more than 200 species of fungi. The most potent are members of the genus ''Psilocybe'', such as '' P. azurescens'', '' P. semilanceata'', and '' P.&nbs ...
– 5-HT2A receptor agoni


Atypical antipsychotics

* Brilaroxazine (RP-5063, RP-5000) – AA – specifically under development for the treatment of MDD * Cariprazine (Reagila, Vraylar) – AA – approved for bipolar depression, under development for MD

* Lumateperone (ITI-007) – AA – specifically under development for the treatment of MDD and bipolar depression * Lurasidone (Latuda) – AA – specifically under development for the treatment of MD

* Pimavanserin (Nuplazid; ACP-103; BVF-048) – 5-HT2A receptor antagonist – specifically under development for the treatment of MDD


Others

* Ademetionine (SAMe; MSI-190, MSI-195, Strada) – cofactor in
monoamine neurotransmitter Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin. All monoamines ar ...
biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecul ...
– specifically under development in the
United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country Continental United States, primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., ...
and
Europe Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...
for the adjunctive treatment of MDD


GABAergics and neurosteroids


GABAA receptor positive modulators

* Zuranolone (SAGE-217) – GABAA receptor positive allosteric modulator – specifically under development for the treatment of MDD and postpartum depression


Others

* 3β-Methoxypregnenolone (MAP-4343) – selective microtubule-associated protein 2 (MAP2) stimulant * Itruvone (PH-10) – vomeropherine (precise mechanism of action unknown/undisclosed)


Opioidergics


κ-Opioid receptor antagonists

* Aticaprant (JNJ-67953964, CERC-501, LY-2456302) – selective
κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind ...
antagonist * BTRX-335140 (BTRX-140) – selective k-opioid receptor antagonist *
Buprenorphine/samidorphan Buprenorphine/samidorphan (developmental code name ALKS-5461) is a combination formulation of buprenorphine and samidorphan which is under development as an add on to antidepressants in treatment-resistant depression (TRD). ALKS-5461 failed to ...
(ALKS-5461) – κ-opioid receptor antagonist and
μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...
antagonist


Nociceptin receptor antagonists

* BTRX-246040 (LY-2940094) –
nociceptin receptor The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the ''OPRL1'' (opioid receptor-like 1) gene. The nociceptin receptor ...
antagonist


Cholinergics


Muscarinic acetylcholine receptor modulators

*
Scopolamine Scopolamine, also known as hyoscine, or Devil's Breath, is a natural or synthetically produced tropane alkaloid and anticholinergic drug that is formally used as a medication for treating motion sickness and postoperative nausea and vomi ...
(DPI-386) – muscarinic acetylcholine receptor antagonistbr>


Others

* Botulinum toxin, OnabotulinumtoxinA (botulinum toxin A, Botox) –
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
release inhibitor – specifically under development for the treatment of MDD in women as a local injection to paralyze facial muscles


Orexin receptor antagonists

* JNJ-61393215 (JNJ-3215; Orexin-1) – OX1 receptor antagonist * Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – OX2 receptor antagonist


Others

* BI-1358894 –
TRPC4 The short transient receptor potential channel 4 (TrpC4), also known as Trp-related protein 4, is a protein that in humans is encoded by the ''TRPC4'' gene. Function TrpC4 is a member of the transient receptor potential cation channels. This ...
and
TRPC5 Short transient receptor potential channel 5 (TrpC5) also known as transient receptor protein 5 (TRP-5) is a protein that in humans is encoded by the ''TRPC5'' gene. TrpC5 is subtype of the TRPC family of mammalian transient receptor potential io ...
inhibito

* Crisdesalazine (AAD-2004) – MPGES-1 inhibito

* Erteberel – selective ERβ receptor agonis

* JNJ-54175446 – P2RX7 purinoceptor antagonist *
NSI-189 NSI-189 is an experimental, potential antidepressant that was developed by Neuralstem, Inc. for the treatment for major depressive disorder (MDD), as well as for cognitive impairment and neurodegeneration. A phase II clinical trial for MDD fai ...
– hippocampal neurotrophic agent (precise
mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targ ...
unknown) *
NV-5138 NV-5138 is an orally and centrally active small-molecule drug which is under development by Navitor Pharmaceuticals for the treatment of major depressive disorder (MDD). It directly and selectively activates the mammalian target of rapamycin c ...
–
sestrin2 Sestrin-2 also known as Hi95 is a protein that in humans is encoded by the ''SESN2'' gene. Function This gene encodes a member of the sestrin family of PA26-related proteins. The encoded protein may function in the regulation of cell growth and ...
modulator and consequent
mammalian target of rapamycin complex 1 mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis. mTOR Complex 1 (mTORC1) is compo ...
(mTORC1) activator * SNG-12 – undefined mechanism of actio

* TS-121 – vasopressin 1B receptor antagonist * WIP-DF17 – undefined mechanism of actio

* XEN1101 - KCNQ2/3 channel opener


Mixed

*
Tramadol Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an ...
(ETS6103; Viotra) –
μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...
agonist,
serotonin–norepinephrine reuptake inhibitor Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs used to treat major depressive disorder (MDD), anxiety disorders, obsessive–compulsive disorder (OCD), social phobia, attention-deficit hyperactivity di ...
(SNRI) and possible
serotonin releasing agent A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter e ...
(SRA), 5-HT2C receptor antagonist, and other actions


Combinations

*
Carbidopa/oxitriptan Carbidopa/oxitriptan (developmental code name EVX-101), or carbidopa/5-hydroxytryptophan (carbidopa/5-HTP), is a combination of 5-hydroxytryptophan (oxitriptan), a serotonin precursor, and carbidopa, a peripherally selective aromatic L-amino ac ...
(EVX-101) – serotonin precursor and aromatic L-amino acid decarboxylase inhibitorbr>
* Cycloserine/lurasidone (NRX-101; Cyclurad) – NMDA receptor glycine site partial agonist and AA combination – specifically under development for the treatment of bipolar depression * Deudextromethorphan/quinidine (AVP-786, CTP-786) – σ1 receptor agonist, SRI, uncompetitive NMDA receptor antagonist, and other actions


Not under development

The following notable drugs are of investigational interest as potential antidepressants but are not formally under clinical development for approval at this time: *
Hydroxynorketamine Hydroxynorketamine (HNK), or 6-hydroxynorketamine, is a minor metabolite of the anesthetic, dissociative, and antidepressant drug ketamine. It is formed by hydroxylation of the intermediate norketamine, another metabolite of ketamine. As of l ...
((2''R'',6''R'')-HNK) – metabolite of ketamine which may be involved in ketamine's antidepressant-like effects in mice * Minocycline –
microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...
inhibitor and other actions; a 2018
systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on t ...
and
meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...
reported that the overall antidepressant
effect size In statistics, an effect size is a value measuring the strength of the relationship between two variables in a population, or a sample-based estimate of that quantity. It can refer to the value of a statistic calculated from a sample of data, the ...
of minocycline compared to
placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...
was -0.78 ( 95% CI: -0.4 to -1.33, P=0.005), indicative of a large and statistically significant antidepressant effect *
Nitrous oxide Nitrous oxide (dinitrogen oxide or dinitrogen monoxide), commonly known as laughing gas, nitrous, or nos, is a chemical compound, an oxide of nitrogen with the formula . At room temperature, it is a colourless non-flammable gas, and ha ...
– NMDA receptor antagonist and other actions * R13 – an
orally active Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are in ...
prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...
of
tropoflavin Tropoflavin, also known as 7,8-dihydroxyflavone, is a naturally occurring flavone found in '' Godmania aesculifolia'', '' Tridax procumbens'', and primula tree leaves. It has been found to act as a potent and selective small-molecule agonist of ...
with improved
pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
*
Tropoflavin Tropoflavin, also known as 7,8-dihydroxyflavone, is a naturally occurring flavone found in '' Godmania aesculifolia'', '' Tridax procumbens'', and primula tree leaves. It has been found to act as a potent and selective small-molecule agonist of ...
(7,8-dihydroxyflavone; 7,8-DHF) – TrkB agonist


See also

*
List of antidepressants This is a complete list of clinically approved prescription antidepressants throughout the world, as well as clinically approved prescription drugs used to augment antidepressants or mood stabilizers, by pharmacological and/or structural classific ...
* List of investigational drugs


References


Further reading

* * *


External links


AdisInsight - Springer
{{Mood stabilizers Antidepressants Antidepressants, investigational Experimental drugs Mood stabilizers